[4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1h-quinoxalin-7-yl)phenoxy]ethyloxy  compound or salt thereof

ABSTRACT

The present invention relates to defined quinoxalin-2-one compounds or a pharmaceutically acceptable salt or a hydrate or a solvate thereof. The compounds, salts or hydrates have a glucocorticoid receptor agonist activity, and are useful as a medicine, in particular as a prophylactic or therapeutic agent for a glucocorticoid receptor related disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/210,163, filed Dec. 5, 2018, which is a continuation of U.S.application Ser. No. 15/753,410, filed Feb. 19, 2018, which issued asU.S. Pat. No. 10,189,796 on Jan. 29, 2019, which is a U.S. NationalStage Application of PCT/JP2016/074863, filed Aug. 25, 2016, whichclaims priority to Japanese Patent Application No. 2015-166247, filedAug. 25, 2015, the contents of all of which are hereby incorporated byreference.

TECHNICAL FIELD

The present invention relates to a novel[4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxycompound or a salt thereof. The compound of the present invention or asalt thereof has a glucocorticoid receptor agonist activity, and usefulas a medicament, in particular, as a prophylactic or therapeutic agentfor a glucocorticoid receptor related disease.

BACKGROUND ART

A glucocorticoid receptor is a 94 kDa ligand-activated intracellulartranscriptional factor that is a member of the nuclear receptorsuperfamily. This receptor is known to regulate the metabolism ofcarbohydrates, proteins, fats and the like, suppress the immune orinflammatory responses, activate the central nervous system, regulatecardiovascular function, and affect basal and stress-related homeostasisand the like due to its transcriptional regulatory action (Non-PatentDocument 1, Patent Document 1).

Therefore, a compound having a glucocorticoid receptor binding activity,in particular, a compound having an agonist action to the glucocorticoidreceptor (hereinafter also referred to as “the glucocorticoid receptoragonist”) is considered to be useful as a prophylactic and/ortherapeutic agent for these diseases.

Patent Document 2 discloses 1,2,3,4-tetrahydroquinoxalinone derivativeswhich are glucocorticoid receptor modulators.

Patent Document 3 discloses1,3,3-trimethyl-7-phenyl-3,4-dihydro-1H-quinoxalin-2-one derivativeswhich are glucocorticoid receptor agonists.

However, the[4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxycompound or a salt thereof is not specifically disclosed in any of thedocuments.

PRIOR ART DOCUMENT Patent Document

-   Patent Document 1: JP 2002-193955A-   Patent Document 2: JP 2008-74829A-   Patent Document 3: JP 2009-84273A

Non-Patent Document

-   Non-Patent Document 1: Clinic All-Round, 54 (7), 1951-2076 (2005)

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

It is a very interesting subject to provide a novel[4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxycompound or a salt thereof.

Means to Solve the Problems

The present inventors conducted studies of synthesis of[4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxycompound or a salt thereof, and succeeded in producing a large number ofnovel compounds. Further, the present inventors studied thepharmacological actions of the compounds, and as a result, they foundthat the[4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]-ethyloxycompound or a salt thereof has a glucocorticoid receptor agonistactivity and are useful as a medicament, and thus the present inventionhas been completed.

The present invention relates to a compound represented by the followinggeneral formula (1) or a salt thereof (hereinafter referred to as “thepresent compound”) and a pharmaceutical composition comprising the same.Further, a preferred invention in its pharmaceutical use relates to aglucocorticoid receptor agonist, and its target diseases areglucocorticoid receptor related diseases, that is, endocrine diseases,collagen diseases, kidney diseases, heart diseases, allergic diseases,blood diseases, digestive system diseases, liver diseases, pulmonarydiseases, severe infectious diseases, tuberculosis disease, nervousdisease, malignant tumor, digestive organ symptoms accompanied byadministration of an anti-malignant tumor agent, surgery relateddiseases, obstetrics and gynecology related diseases, urology relateddiseases, skin diseases, otolaryngology related diseases, oral surgeryrelated diseases, glaucoma, rheumatic diseases, inflammatory diseasesand the like. A particularly preferred invention is an inventionrelating to a prophylactic or a therapeutic agent for these diseases. Inaddition, the present invention also relates to use of the presentcompound for the prophylaxis or treatment of these diseases, use of thepresent compound for the manufacture of a medicament for the prophylaxisor treatment of these diseases, and a method for the prophylaxis ortreatment of these diseases, which comprises administering an effectiveamount of the present compound.

[wherein R¹ represents a hydrogen atom, a lower alkyl group which mayhave a substituent(s), a carboxyl group, an ester of a carboxyl group,an amide of a carboxyl group or a cyano group;R² represents a hydrogen atom, a lower alkylcarbonyl group which mayhave a substituent(s), a lower cycloalkylcarbonyl group which may have asubstituent(s), an arylcarbonyl group which may have a substituent(s), aheterocyclic carbonyl group which may have a substituent(s), an ester ofa carboxyl group, an amide of a carboxyl group, a phosphate group or anester of a phosphate group.]

That is, the present invention relates to the following.

Item 1. A compound represented by the following general formula (1) or asalt thereof.

[wherein R¹ represents a hydrogen atom, a lower alkyl group which mayhave a substituent(s), a carboxyl group, an ester of a carboxyl group,an amide of a carboxyl group or a cyano group; andR² represents a hydrogen atom, a lower alkylcarbonyl group which mayhave a substituent(s), a lower cycloalkylcarbonyl group which may have asubstituent(s), an arylcarbonyl group which may have a substituent(s), aheterocyclic carbonyl group which may have a substituent(s), an ester ofa carboxyl group, an amide of a carboxyl group, a phosphate group or anester of a phosphate group.]Item 2. The compound or a salt thereof described in Item 1, wherein, inthe general formula (1),

R¹ represents a hydrogen atom, a lower alkyl group, a carboxyl group, anester of a carboxyl group, an amide of a carboxyl group or a cyanogroup;

in the case where R¹ is a lower alkyl group, the lower alkyl group mayhave one or a plurality of groups selected from a halogen atom, a lowercycloalkyl group, an aryl group, a heterocyclic group, a hydroxyl group,an ester of a hydroxyl group, a lower alkoxyl group, a lower alkoxylgroup substituted by a halogen atom(s), a lower cycloalkyloxy group, anaryloxy group, a heterocyclicoxy group, an amino group, a loweralkylamino group, a lower cycloalkylamino group, an arylamino group, aheterocyclic amino group, an amide of an amino group, an amide of alower alkylamino group, an amide of a lower cycloalkylamino group, anamide of an arylamino group, an amide of a heterocyclic amino group, alower alkylcarbonyl group, a lower cycloalkylcarbonyl group, anarylcarbonyl group, a heterocyclic carbonyl group, a carboxyl group, anester of a carboxyl group, an amide of a carboxyl group and a cyanogroup as a substituent(s);

R² represents a hydrogen atom, a lower alkylcarbonyl group, a lowercycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonylgroup, a carboxyl group, an ester of a carboxyl group, an amide of acarboxyl group, a phosphate group or an ester of a phosphate group; and

in the case where R² is a lower alkylcarbonyl group, a lowercycloalkyl-carbonyl group, an arylcarbonyl group or a heterocycliccarbonyl group, the lower alkylcarbonyl group, the lowercycloalkylcarbonyl group, the arylcarbonyl group or the heterocycliccarbonyl group may have one or a plurality of groups selected from ahalogen atom, a lower cycloalkyl group, an aryl group, a heterocyclicgroup, a hydroxyl group, an ester of a hydroxyl group, a lower alkoxylgroup, a lower alkoxyl group substituted by a halogen atom(s), a lowercycloalkyloxy group, an aryloxy group, a heterocyclicoxy group, an aminogroup, a lower alkylamino group, a lower cycloalkyl-amino group, anarylamino group, a heterocyclic amino group, an amide of an amino group,an amide of a lower alkylamino group, an amide of a lowercycloalkylamino group, an amide of an arylamino group, an amide of aheterocyclic amino group, a lower alkylcarbonyl group, a lowercycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonylgroup, a carboxyl group, an ester of a carboxyl group, an amide of acarboxyl group and a cyano group as a substituent(s).

Item 3. The compound or a salt thereof described in Item 1, wherein, inthe general formula (1),

R¹ represents a hydrogen atom, a lower alkyl group, a carboxyl group oran ester of a carboxyl group;

in the case where R¹ is a lower alkyl group, the lower alkyl group mayhave one or a plurality of groups selected from a halogen atom, ahydroxyl group, a lower alkoxyl group, a lower alkylcarbonyl group, acarboxyl group, an ester of a carboxyl group, an amide of a carboxylgroup and a cyano group as a substituent(s);

R² represents a hydrogen atom, a lower alkylcarbonyl group, aheterocyclic carbonyl group, a phosphate group or an ester of aphosphate group; and

in the case where R² is a lower alkylcarbonyl group, the loweralkylcarbonyl group may have one or a plurality of groups selected froma halogen atom, a hydroxyl group, an ester of a hydroxyl group, a loweralkoxyl group, a lower alkoxyl group substituted by a halogen atom(s),an amino group, a lower alkylamino group, a lower alkylcarbonyl group, acarboxyl group, an ester of a carboxyl group, an amide of a carboxylgroup and a cyano group as a substituent(s).

Item 4. The compound or a salt thereof described in Item 1, wherein inthe general formula (1), R¹ represents a hydrogen atom, a lower alkylgroup or an ester of a carboxyl group;

in the case where R¹ is a lower alkyl group, the lower alkyl group mayhave one or a plurality of groups selected from a halogen atom, ahydroxyl group, a carboxyl group, an ester of a carboxyl group, an amideof a carboxyl group and a cyano group as a substituent(s);

R² represents a hydrogen atom, a lower alkylcarbonyl group, aheterocyclic carbonyl group or a phosphate group; and

in the case where R² is a lower alkylcarbonyl group, the loweralkylcarbonyl group may have one or a plurality of groups selected froma hydroxyl group, an amino group, a lower alkylamino group and acarboxyl group as a substituent(s).

Item 5. The compound or a salt thereof described in Item 1, wherein, inthe general formula (1), R¹ represents a lower alkyl group;

the lower alkyl group may have one or a plurality of hydroxyl groups asa substituent(s);

R² represents a hydrogen atom or a lower alkylcarbonyl group; and

in the case where R² is a lower alkylcarbonyl group, the loweralkylcarbonyl group may have one or a plurality of lower alkylaminogroups as a substituent(s).

Item 6. The compound or a salt thereof described in Item 1, wherein inthe general formula (1), R¹ represents methyl or 1-hydroxyethyl; and

R² represents a hydrogen atom or dimethylaminomethylcarbonyl.

Item 7. A compound selected from the group consisting of

-   (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   S8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxy-3,3,3-trifluoropropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-7-[4-(2-ethoxycarbonyl-2-hydroxyethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxyacetoxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxyethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-7-[4-(3-cyano-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-(3-cyano-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-(3-fluoro-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-(3-ethoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-(3-t-butoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-(3,3-dimethyl-2-hydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-(3-carboxy-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-pyrrolidylcarbonyl)-2-hydroxy-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-morpholino)carbonyl-2-hydroxy-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-piperidino)carbonyl-2-hydroxy-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-[2-(N,N-dimethylaminoacetoxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[(2S)-[(2S)-pyrrolidylcarbonyloxy]-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-7-[4-[2-(N,N-dimethylaminoacetoxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-(2-aminoacetoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-[(2S)-[(2S)-amino-3-methylbutanoyloxy]propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-[2-(3-carboxypropanoyloxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-[2-(2,3-dihydroxypropanoyl)oxypropyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-[(2S)-[(2S)-amino-3-hydroxypropanoyloxy]propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-phosphonohydroxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-phosphonohydroxybutyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one    and,-   (S)-7-[4-(3-cyano-2-phosphonohydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one    or a salt thereof.    Item 8. A pharmaceutical composition comprising the compound or a    salt thereof described in any one of Items 1 to 7.    Item 9. A glucocorticoid receptor agonist comprising the compound or    a salt thereof described in any one of Items 1 to 7 as an active    ingredient.    Item 10. A glucocorticoid receptor activator comprising the compound    or a salt thereof described in any one of Items 1 to 7 as an active    ingredient.    Item 11. A prophylactic or therapeutic agent for a glucocorticoid    receptor related disease, which comprises the compound or a salt    thereof described in any one of Items 1 to 7 as an active    ingredient.    Item 12. The prophylactic or therapeutic agent described in Item 11,    wherein the glucocorticoid receptor related disease is at least one    selected from the group consisting of endocrine diseases, collagen    diseases, kidney diseases, heart diseases, allergic diseases, blood    diseases, digestive system diseases, liver diseases, pulmonary    diseases, severe infectious diseases, tuberculosis disease, nervous    disease, malignant tumor, digestive organ symptoms accompanied by    administration of an anti-malignant tumor agent, surgery related    diseases, obstetrics and gynecology related diseases, urology    related diseases, skin diseases, otolaryngology related diseases,    oral surgery related diseases, glaucoma, rheumatic diseases and    inflammatory diseases.    Item 13. The prophylactic or therapeutic agent described in Item 12,    wherein the inflammatory disease is at least one selected from the    group consisting of inflammatory bone or joint disease, ocular    inflammatory disease, asthma, bronchitis, rhinitis, dermatitis and    inflammatory bowel disease.    Item 14. The prophylactic or therapeutic agent described in Item 13,    wherein the inflammatory bone or joint disease is at least one    selected from the group consisting of rheumatoid arthritis, juvenile    rheumatoid arthritis, osteoarthritis, osteoporosis and    spondylarthritis.    Item 15. The prophylactic or therapeutic agent described in Item 13,    wherein the ocular inflammatory disease is an anterior eye    inflammatory disease.    Item 16. The prophylactic or therapeutic agent described in Item 13,    wherein the ocular inflammatory disease is a posterior eye    inflammatory disease.    Item 17. The prophylactic or therapeutic agent described in Item 15,    wherein the anterior eye inflammatory disease is at least one    selected from the group consisting of keratitis,    keratoconjunctivitis, conjunctivitis, blepharitis, dry eye syndrome,    allergic conjunctivitis, uveitis, inflammation after anterior eye    surgery and inflammation due to rejection of ocular tissue    transplantation.    Item 18. The prophylactic or therapeutic agent described in Item 16,    wherein the posterior eye inflammatory disease is at least one    selected from the group consisting of age-related macular    degeneration, diabetic retinopathy, diabetic macular edema,    neovascular maculopathy, proliferative vitreoretinopathy, central    retinal vein occlusion, central retinal artery occlusion, branch    retinal vein occlusion, branch retinal artery occlusion,    inflammation or degeneration of posterior eye caused by external    injury, retinitis, uveitis, scleritis and optic neuritis.    Item 19. The compound or a salt thereof described in any one of    Items 1 to 7 for use in the prophylaxis or treatment of a    glucocorticoid receptor related disease.    Item 20. The compound or a salt thereof described in Item 19,    wherein the glucocorticoid receptor related disease is at least one    selected from the group consisting of endocrine diseases, collagen    diseases, kidney diseases, heart diseases, allergic diseases, blood    diseases, digestive system diseases, liver diseases, pulmonary    diseases, severe infectious diseases, tuberculosis disease, nervous    disease, malignant tumor, digestive organ symptoms accompanied by    administration of an anti-malignant tumor agent, surgery related    diseases, obstetrics and gynecology related diseases, urology    related diseases, skin diseases, otolaryngology related diseases,    oral surgery related diseases, glaucoma, rheumatic diseases and    inflammatory diseases.    Item 21. The compound or a salt thereof described in Item 20,    wherein the inflammatory disease is at least one selected from the    group consisting of inflammatory bone or joint disease, ocular    inflammatory diseases, asthma, bronchitis, rhinitis, dermatitis and    inflammatory bowel disease.    Item 22. The compound or a salt thereof described in Item 21,    wherein the inflammatory bone or joint disease is at least one    selected from the group consisting of rheumatoid arthritis, juvenile    rheumatoid arthritis, osteoarthritis, osteoporosis and    spondylarthritis.    Item 23. The compound or a salt thereof described in Item 21,    wherein the ocular inflammatory disease is an anterior eye    inflammatory disease.    Item 24. The compound or a salt thereof described in Item 21,    wherein the ocular inflammatory disease is a posterior eye    inflammatory disease.    Item 25. The compound or a salt thereof described in Item 23,    wherein the anterior eye inflammatory disease is at least one    selected from the group consisting of keratitis,    keratoconjunctivitis, conjunctivitis, blepharitis, dry eye syndrome,    allergic conjunctivitis, uveitis, inflammation after anterior eye    surgery and inflammation due to rejection of ocular tissue    transplantation.    Item 26. The compound or a salt thereof described in Item 24,    wherein the posterior eye inflammatory disease is at least one    selected from the group consisting of age-related macular    degeneration, diabetic retinopathy, diabetic macular edema,    neovascular maculopathy, proliferative vitreoretinopathy, central    retinal vein occlusion, central retinal artery occlusion, branch    retinal vein occlusion, branch retinal artery occlusion,    inflammation or degeneration of posterior eye caused by external    injury, retinitis, uveitis, scleritis and optic neuritis.    Item 27. Use of the compound or a salt thereof described in any one    of Items 1 to 7 for the use of the manufacture of a medicament for    the prophylaxis or treatment of a glucocorticoid receptor related    disease.    Item 28. The use of Item 27, wherein the glucocorticoid receptor    related disease is at least one selected from the group consisting    of endocrine diseases, collagen diseases, kidney diseases, heart    diseases, allergic diseases, blood diseases, digestive system    diseases, liver diseases, pulmonary diseases, severe infectious    diseases, tuberculosis disease, nervous disease, malignant tumor,    digestive organ symptoms accompanied by administration of an    anti-malignant tumor agent, surgery related diseases, obstetrics and    gynecology related diseases, urology related diseases, skin    diseases, otolaryngology related diseases, oral surgery related    diseases, glaucoma, rheumatic diseases and inflammatory diseases.    Item 29. The use described in Item 28, wherein the inflammatory    disease is at least one selected from the group consisting of    inflammatory bone or joint disease, ocular inflammatory disease,    asthma, bronchitis, rhinitis, dermatitis and inflammatory bowel    disease.    Item 30. The use described in Item 29, wherein the inflammatory bone    or joint disease is at least one selected from the group consisting    of rheumatoid arthritis, juvenile rheumatoid arthritis,    osteoarthritis, osteoporosis and spondylarthritis.    Item 31. The use described in Item 29, wherein the ocular    inflammatory disease is an anterior eye inflammatory disease.    Item 32. The use described in Item 29, wherein the ocular    inflammatory disease is a posterior eye inflammatory disease.    Item 33. The use described in Item 31, wherein the anterior eye    inflammatory disease is at least one selected from the group    consisting of keratitis, keratoconjunctivitis, conjunctivitis,    blepharitis, dry eye syndrome, allergic conjunctivitis, uveitis,    inflammation after anterior eye surgery and inflammation due to    rejection of ocular tissue transplantation.    Item 34. The use described in Item 32, wherein the posterior eye    inflammatory disease is at least one selected from the group    consisting of age-related macular degeneration, diabetic    retinopathy, diabetic macular edema, neovascular maculopathy,    proliferative vitreoretinopathy, central retinal vein occlusion,    central retinal artery occlusion, branch retinal vein occlusion,    branch retinal artery occlusion, inflammation or degeneration of    posterior eye caused by external injury, retinitis, uveitis,    scleritis and optic neuritis.    Item 35. A method for the prophylaxis or treatment of a    glucocorticoid receptor related disease, which comprises    administering an effective amount of the compound or a salt thereof    described in any one of Items 1 to 7.    Item 36. The method for the prophylaxis or treatment described in    Item 35, wherein the glucocorticoid receptor related disease is at    least one selected from the group consisting of endocrine diseases,    collagen diseases, kidney diseases, heart diseases, allergic    diseases, blood diseases, digestive system diseases, liver diseases,    pulmonary diseases, severe infectious diseases, tuberculosis    disease, nervous disease, malignant tumor, digestive organ symptoms    accompanied by administration of an anti-malignant tumor agent,    surgery related diseases, obstetrics and gynecology related    diseases, urology related diseases, skin diseases, otolaryngology    related diseases, oral surgery related diseases, glaucoma, rheumatic    diseases and inflammatory diseases.    Item 37. The method for the prophylaxis or treatment described in    Item 36, wherein the inflammatory disease is at least one selected    from the group consisting of inflammatory bone or joint disease,    ocular inflammatory disease, asthma, bronchitis, rhinitis,    dermatitis and inflammatory bowel disease.    Item 38. The method for the prophylaxis or treatment described in    Item 37, wherein the inflammatory bone or joint disease is at least    one selected from the group consisting of rheumatoid arthritis,    juvenile rheumatoid arthritis, osteoarthritis, osteoporosis and    spondylarthritis.    Item 39. The method for the prophylaxis or treatment described in    Item 37, wherein the ocular inflammatory disease is an anterior eye    inflammatory disease.    Item 40. The method for the prophylaxis or treatment described in    Item 37, wherein the ocular inflammatory disease is a posterior eye    inflammatory disease.    Item 41. The method for the prophylaxis or treatment described in    Item 39, wherein the anterior eye inflammatory disease is at least    one selected from the group consisting of keratitis,    keratoconjunctivitis, conjunctivitis, blepharitis, dry eye syndrome,    allergic conjunctivitis, uveitis, inflammation after anterior eye    surgery and inflammation due to rejection of ocular tissue    transplantation.    Item 42. The method for the prophylaxis or treatment described in    Item 40, wherein the posterior eye inflammatory disease is at least    one selected from the group consisting of age-related macular    degeneration, diabetic retinopathy, diabetic macular edema,    neovascular maculopathy, proliferative vitreoretinopathy, central    retinal vein occlusion, central retinal artery occlusion, branch    retinal vein occlusion, branch retinal artery occlusion,    inflammation or degeneration of posterior eye caused by external    injury, retinitis, uveitis, scleritis and optic neuritis.    Item 43. A pharmaceutical composition for the prophylaxis or    treatment of a glucocorticoid receptor related disease, which    comprises the compound or a salt thereof described in any one of    Items 1 to 7 as an active ingredient.    Item 44. The pharmaceutical composition for the prophylaxis or    treatment described in Item 43, wherein the glucocorticoid receptor    related disease is at least one selected from the group consisting    of endocrine diseases, collagen diseases, kidney diseases, heart    diseases, allergic diseases, blood diseases, digestive system    diseases, liver diseases, pulmonary diseases, severe infectious    diseases, tuberculosis disease, nervous disease, malignant tumor,    digestive organ symptoms accompanied by administration of an    anti-malignant tumor agent, surgery related diseases, obstetrics and    gynecology related diseases, urology related diseases, skin    diseases, otolaryngology related diseases, oral surgery related    diseases, glaucoma, rheumatic diseases and inflammatory diseases.    Item 45. The pharmaceutical composition for the prophylaxis or    treatment described in Item 44, wherein the inflammatory disease is    at least one selected from the group consisting of inflammatory bone    or joint disease, ocular inflammatory disease, asthma, bronchitis,    rhinitis, dermatitis and inflammatory bowel disease.    Item 46. The pharmaceutical composition for the prophylaxis or    treatment described in Item 45, wherein the inflammatory bone or    joint disease is at least one selected from the group consisting of    rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis,    osteoporosis and spondylarthritis.    Item 47. The pharmaceutical composition for the prophylaxis or    treatment described in Item 45, wherein the ocular inflammatory    disease is an anterior eye inflammatory disease.    Item 48. The pharmaceutical composition for the prophylaxis or    treatment described in Item 45, wherein the ocular inflammatory    disease is a posterior eye inflammatory disease.    Item 49. The pharmaceutical composition for the prophylaxis or    treatment described in Item 47, wherein the anterior eye    inflammatory disease is at least one selected from the group    consisting of keratitis, keratoconjunctivitis, conjunctivitis,    blepharitis, dry eye syndrome, allergic conjunctivitis, uveitis,    inflammation after anterior eye surgery and inflammation due to    rejection of ocular tissue transplantation.    Item 50. The pharmaceutical composition for the prophylaxis or    treatment described in Item 48, wherein the posterior eye    inflammatory disease is at least one selected from the group    consisting of age-related macular degeneration, diabetic    retinopathy, diabetic macular edema, neovascular maculopathy,    proliferative vitreoretinopathy, central retinal vein occlusion,    central retinal artery occlusion, branch retinal vein occlusion,    branch retinal artery occlusion, inflammation or degeneration of    posterior eye caused by external injury, retinitis, uveitis,    scleritis and optic neuritis.

Effects of the Invention

The present invention can provide a novel[4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxycompound or a salt thereof. The compound of the present invention hasexcellent glucocorticoid receptor agonist activity, and is useful as amedicament, in particular, as a prophylactic or therapeutic agent forglucocorticoid receptor related disease, i.e., endocrine diseases,collagen diseases, kidney diseases, heart diseases, allergic diseases,blood diseases, digestive system diseases, liver diseases, pulmonarydiseases, severe infectious diseases, tuberculosis disease, nervousdisease, malignant tumor, digestive organ symptoms accompanied byadministration of an anti-malignant tumor agent, surgery relateddiseases, obstetrics and gynecology related diseases, urology relateddiseases, skin diseases, otolaryngology related diseases, oral surgeryrelated diseases, glaucoma, rheumatic diseases, inflammatory diseases,etc.

EMBODIMENTS TO CARRY OUT THE INVENTION

Hereinafter, definitions of terms (atoms, groups, rings and the like) tobe used in this specification will be described in detail.

The “halogen atom” refers to a fluorine, chlorine, bromine or iodineatom.

The “lower alkyl group” refers to a straight chain or branched alkylgroup having 1 to 8, preferably 1 to 6, and particularly preferably 1 to4 carbon atoms. Specific examples thereof include methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl,isobutyl, sec-butyl, tert-butyl and isopentyl groups and the like.

The “lower cycloalkyl group” refers to a cycloalkyl group having 3 to 8,preferably 3 to 6 carbon atoms. Specific examples thereof includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl groups.

The “aryl group” refers to a residue formed by removing one hydrogenatom from a monocyclic aromatic hydrocarbon group, or bicyclic ortricyclic condensed polycyclic aromatic hydrocarbon having 6 to 14carbon atoms. Specific examples thereof include phenyl, naphthyl,anthryl and phenanthryl groups and the like.

The “heterocyclic group” refers to a residue formed by removing onehydrogen atom from a saturated or unsaturated monocyclic heterocyclicring (preferably, a saturated or unsaturated monocyclic hetero 5 or6-membered ring having 3 to 5 carbon atoms, which has one or twoheteroatoms in the ring), or a bicyclic or tricyclic condensedpolycyclic heterocyclic ring (preferably, a bicyclic or tricycliccondensed polycyclic hetero ring having 7 to 13 carbon atoms, which hasone or two heteroatoms in the ring) having one or a plurality ofheteroatoms selected from a nitrogen atom, an oxygen atom and a sulfuratom in the ring.

Specific examples of the saturated monocyclic heterocyclic ring includepyrrolidine, pyrazolidine, imidazolidine, triazolidine, piperidine,hexahydropyridazine, hexahydropyrimidine, piperazine, homopiperidine andhomopiperazine rings and the like having nitrogen atom in the ring,tetrahydrofuran and tetrahydropyran rings and the like having oxygenatom in the ring, tetrahydrothiophene and tetrahydrothiopyran rings andthe like having a sulfur atom in the ring, oxazolidine, isoxazolidineand morpholine rings and the like having nitrogen atom and oxygen atomin the ring, and thiazolidine, isothiazolidine and thiomorpholine ringsand the like having nitrogen atom and sulfur atom in the ring.

Further, such a saturated monocyclic heterocyclic ring can be condensedwith a benzene ring or the like to form a bicyclic or tricycliccondensed polycyclic heterocyclic ring such as a dihydroindole,dihydroindazole, dihydrobenzimidazole, tetrahydro-quinoline,tetrahydroisoquinoline, tetrahydrocinnoline, tetrahydrophthalazine,tetrahydroquinazoline, tetrahydroquinoxaline, dihydrobenzofuran,dihydroisobenzo-furan, chromane, isochromane, dihydrobenzothiophene,dihydroisobenzothiophene, thiochromane, isothiochromane,dihydrobenzoxazole, dihydrobenzisoxazole, dihydrobenzoxazine,dihydrobenzothiazole, dihydrobenzisothiazole, dihydrobenzo-thiazine,xanthene, 4a-carbazole, or perimidine ring.

Specific examples of the unsaturated monocyclic heterocyclic ringinclude dihydropyrrole, pyrrole, dihydropyrazole, pyrazole,dihydroimidazole, imidazole, dihydrotriazole, triazole,tetrahydropyridine, dihydropyridine, pyridine, tetrahydro-pyridazine,dihydropyridazine, pyridazine, tetrahydropyrimidine, dihydropyrimidine,pyrimidine, tetrahydropyrazine, dihydropyrazine and pyrazine rings andthe like having nitrogen atom in the ring, dihydrofuran, furan,dihydropyran and pyran rings and the like having oxygen atom in thering, dihydrothiophene, thiophene, dihydrothiopyran and thiopyran ringsand the like having sulfur atom in the ring, dihydrooxazole, oxazole,dihydroisoxazole, isoxazole, dihydrooxazine and oxazine rings and thelike having nitrogen atom and oxygen atom in the ring, dihydrothiazole,thiazole, dihydroisothiazole, isothiazole, dihydrothiazine and thiazinerings and the like having nitrogen atom and sulfur atom in the ring.

Further, such an unsaturated monocyclic heterocyclic ring can becondensed with a benzene ring or the like to form a bicyclic ortricyclic condensed polycyclic heterocyclic ring such as an indole,indazole, benzimidazole, benzotriazole, dihydroquinoline, quinoline,dihydroisoquinoline, isoquinoline, phenanthridine, dihydrocinnoline,cinnoline, dihydrophthalazine, phthalazine, dihydroquinazoline,quinazoline, dihydroquinoxaline, quinoxaline, benzofuran, isobenzofuran,chromene, isochromene, benzothiophene, isobenzothiophene, thiochromene,isothiochromene, benzoxazole, benzisoxazole, benzoxazine, benzothiazole,benzisothiazole, benzothiazine, phenoxanthin, carbazole, β-carboline,phenanthridine, acridine, phenanthroline, phenazine, phenothiazine orphenoxazine ring.

The “lower alkoxy group” refers to a group formed by replacing thehydrogen atom of a hydroxyl group with a lower alkyl group. Specificexamples thereof include methoxy, ethoxy, n-propoxy, n-butoxy,n-pentoxy, n-hexyloxy, n-heptyloxy, n-octyl-oxy, isopropoxy, isobutoxy,sec-butoxy, tert-butoxy and isopentoxy groups and the like.

The “lower cycloalkyloxy group” refers to a group formed by replacingthe hydrogen atom of a hydroxyl group with a lower cycloalkyl group.Specific examples thereof include cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy groupsand the like.

The “aryloxy group” refers to a group formed by replacing the hydrogenatom of a hydroxyl group with an aryl group. Specific examples thereofinclude phenoxy, naphthoxy, anthryloxy and phenanthryloxy groups and thelike.

The “heterocyclic oxy group” refers to a group formed by replacing thehydrogen atom of a hydroxyl group with a heterocyclic group. Specificexamples thereof include pyrrolidinyloxy, piperidinyloxy,piperazinyloxy, tetrahydrofuranyloxy, morpholinyloxy, pyrazolyloxy,imidazolyloxy, pyridinyloxy, pyrimidinyloxy, furanyloxy, thiazolyloxy,quinolyloxy, quinazolyloxy, benzofuranyloxy and benzothiazolyloxy groupsand the like.

The “lower alkylamino group” refers to a group formed by replacing oneor both of the hydrogen atoms of an amino group with a lower alkylgroup(s). Specific examples thereof include methylamino, ethylamino,propylamino, dimethylamino, diethylamino and ethyl(methyl)amino groupsand the like.

The “lower cycloalkylamino group” refers to a group formed by replacingone or both hydrogen atoms of an amino group with a lower cycloalkylgroup(s), and in the case where the group represents one formed byreplacing one of the hydrogen atoms of the amino group with a lowercycloalkyl group, the other represents a hydrogen atom or a group inwhich the hydrogen atom is replaced with a lower alkyl group. Specificexamples thereof include cyclopropylamino, cyclobutylamino,cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino,dicyclohexylamino and cyclohexyl(methyl)amino groups and the like.

The “arylamino group” refers to a group formed by replacing one or bothof the hydrogen atoms of amino group with aryl group(s), and in the casewhere the group represents one formed by replacing one of the hydrogenatoms of the amino group with an aryl group, the other represents ahydrogen atom or a group in which the hydrogen atom is replaced with alower alkyl group or lower cycloalkyl group. Specific examples thereofinclude phenylamino, naphthylamino, anthrylamino, phenanthryl-amino,diphenylamino, methyl (phenyl) amino, ethyl (phenyl) amino andcyclohexyl (phenyl) amino groups and the like.

The “heterocyclic amino group” refers to a group formed by replacing oneor both of the hydrogen atoms of amino group with heterocyclic group(s),and in the case where the group represents one formed by replacing oneof the hydrogen atoms of the amino group with a heterocyclic group, theother represents a hydrogen atom or a group in which the hydrogen atomis replaced with a lower alkyl group, lower cycloalkyl group or arylgroup. Specific examples thereof include piperidinylamino,N-methyl-N-piperidinyl amino, N-phenyl-N-piperidinylamino,piperazinylamino, morpholinylamino, N-methyl-N-morpholinyl amino, N-cyclopropyl-N-morpholinylamino, pyridinylamino and N-methyl-N-pyridinylaminogroups and the like.

The “lower alkylcarbonyl group” refers to a group formed by replacingthe hydrogen atom of a formyl group with a lower alkyl group. Specificexamples thereof include methylcarbonyl, ethylcarbonyl,n-propylcarbonyl, n-butylcarbonyl, n-pentyl-carbonyl, n-hexylcarbonyl,n-heptylcarbonyl, n-octylcarbonyl, isopropylcarbonyl, isobutylcarbonyl,sec-butylcarbonyl, tert-butylcarbonyl and isopentylcarbonyl groups andthe like.

The “lower cycloalkylcarbonyl group” refers to a group formed byreplacing the hydrogen atom of a formyl group with a lower cycloalkylgroup. Specific examples thereof include cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentyl-carbonyl, cyclohexylcarbonyl,cycloheptylcarbonyl and cyclooctylcarbonyl groups.

The “arylcarbonyl group” refers to a group formed by replacing thehydrogen atom of a formyl group with an aryl group. Specific examplesthereof include phenylcarbonyl, naphthylcarbonyl, anthrylcarbonyl andphenanthrylcarbonyl groups and the like.

The “heterocyclic carbonyl group” refers to a group formed by replacingthe hydrogen atom of a formyl group with a heterocyclic group. Specificexamples thereof include pyrrolidinylcarbonyl, piperidinylcarbonyl,piperazinylcarbonyl, tetrahydrofuranylcarbonyl, morpholinylcarbonyl,pyrazolylcarbonyl, imidazolyl-carbonyl, pyridinylcarbonyl,pyrimidinylcarbonyl, furanylcarbonyl, thiazolylcarbonyl,quinolylcarbonyl, quinazolylcarbonyl, benzofuranylcarbonyl andbenzothiazolyl-carbonyl group and the like.

The “phosphate group” refers to a group represented by —PO(OH)₂.

The “ester of a hydroxyl group” refers to a group represented by—OCO—R^(a).

Here, “R^(a)” represents a lower alkyl group which may have asubstituent(s), a lower cycloalkyl group which may have asubstituent(s), an aryl group which may have a substituent(s), aheterocyclic group which may have a substituent(s), a lower alkoxy groupwhich may have a substituent(s), a lower cycloalkyloxy group which mayhave a substituent(s), an aryloxy group which may have a substituent(s),a heterocyclicoxy group which may have a substituent(s), an amino group,a lower alkylamino group which may have a substituent(s), a lowercycloalkylamino group which may have a substituent(s), an arylaminogroup which may have a substituent(s) or a heterocyclic amino groupwhich may have a substituent(s). In the following, “R^(a)” is the same.

The “amide of an amino group” refers to a group represented by—NHCO—R^(a). Here, “R^(a)” is the same as mentioned above.

The “amide of a lower alkylamino group” refers to a group represented by—NR^(b)CO—R^(a). Here, “R^(b)” represents a lower alkyl group which mayhave a substituent(s), and “R^(a),” is the same as mentioned above.

The “amide of a lower cycloalkylamino group” refers to a grouprepresented by —NRCCO—R^(a). Here, “R^(c)” represents a lower cycloalkylgroup which may have a substituent(s), and “R^(a)” is the same asmentioned above.

The “amide of an arylamino group” refers to a group represented by—NR^(d)CO—R^(a). Here, “R^(d)” represents an aryl group which may have asubstituent(s), and “R^(a),” is the same as mentioned above.

The “amide of a heterocyclic amino group” refers to a group representedby —NR^(e)CO—R^(a). Here, “R^(e)” represents a heterocyclic group whichmay have a substituent(s), and “R^(a),” is the same as mentioned above.

The “ester of a carboxyl group” refers to a group represented by—COOR^(f). Here, “R^(f)” represents a lower alkyl group which may have asubstituent(s), a lower cycloalkyl group which may have asubstituent(s), an aryl group which may have a substituent(s) or aheterocyclic group which may have a substituent(s).

The “amide of a carboxyl group” refers to a group represented by—CONR^(g)R^(h). Here, “R^(g)” and “R^(h)” may be the same or differentfrom each other, and each represent a hydrogen atom, a lower alkyl groupwhich may have a substituent(s), a lower cycloalkyl group which may havea substituent(s), an aryl group which may have a substituent(s) or aheterocyclic group which may have a substituent(s), or “R^(g)” and“R^(h)” are combined to form a heterocyclic ring.

The “ester of a phosphate group” refers to a group represented by—PO(OR)₂. Here, “R” represents a lower alkyl group.

The “lower alkyl group which may have a substituent(s)”, “loweralkylcarbonyl group which may have a substituent(s)”, “lower alkoxygroup which may have a substituent(s)”, or “a lower alkylamino groupwhich may have a substituent(s)” refer to a “lower alkyl group”, a“lower alkylcarbonyl group”, a “lower alkoxy group”, or “a loweralkylamino group” in which the lower alkyl portion thereof may have oneor a plurality of substituents selected from the following a group,respectively.

The “α group” refers to a halogen atom, a lower cycloalkyl group, anaryl group, a heterocyclic group, a hydroxyl group, an ester of ahydroxyl group, a lower alkoxyl group, a lower alkoxyl group substitutedby a halogen atom(s), a lower cycloalkyloxy group, an aryloxy group, aheterocyclicoxy group, an amino group, a lower alkylamino group, a lowercycloalkylamino group, an arylamino group, a heterocyclic amino group,an amide of an amino group, an amide of a lower alkylamino group, anamide of a lower cycloalkylamino group, an amide of an arylamino group,an amide of a heterocyclic amino group, a lower alkylcarbonyl group, alower cycloalkyl-carbonyl group, an arylcarbonyl group, a heterocycliccarbonyl group, a carboxyl group, an ester of a carboxyl group, an amideof a carboxyl group, a nitro group and a cyano group.

The “lower cycloalkylcarbonyl group which may have a substituent(s)”,the “arylcarbonyl group which may have a substituent(s)”, the“heterocyclic carbonyl group which may have a substituent(s)”, the“lower cycloalkyl group which may have a substituent(s)”, the “arylgroup which may have a substituent(s)”, the “heterocyclic group whichmay have a substituent(s)”, the “cycloalkyloxy group which may have asubstituent(s)”, the “aryloxy group which may have a substituent(s)”,the “heterocyclic-oxy group which may have a substituent(s)”, the“cycloalkylamino group which may have a substituent(s)” or the“arylamino group which may have a substituent(s)” refer to the “lowercycloalkylcarbonyl group which may have a substituent(s)”, the“arylcarbon-yl group which may have a substituent(s)”, the “heterocycliccarbonyl group which may have a substituent(s)”, the “lower cycloalkylgroup which may have a substituent(s)”, the “aryl group which may have asubstituent(s)”, the “heterocyclic group which may have asubstituent(s)”, the “cycloalkyloxy group which may have asubstituent(s)”, the “aryloxy group which may have a substituent(s)”,the “heterocyclicoxy group which may have a substituent(s)”, the“cycloalkylamino group which may have a substi-tuent(s)” or the“arylamino group which may have a substituent(s)” in which the lowercycloalkyl portion thereof, the aryl portion, and the heterocyclicportion may have one or a plurality of substituents selected from theabove-mentioned a group, respectively.

The term “a plurality of groups” as used in the present invention meansthat each group may be the same or different and the number of groups istwo or more at the site to be substituted and the number ofsubstitutable groups or less, and the number is preferably in the caseof 2 or 3. Further, a hydrogen atom and a halogen atom are also includedin the concept of the “group”.

The “salt” of the present compound is not particularly limited as longas it is a pharmaceutically acceptable salt. There may be mentioned, forexample, salts with an inorganic acid such as hydrochloric acid,hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid orphosphoric acid; salts with an organic acid such as acetic acid, fumalicacid, maleic acid, succinic acid, citric acid, tartaric acid, adipicacid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalicacid, methanesulfonic acid, lactic acid, hippuric acid,1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleicacid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid,trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, lauryl sulfate ester, methyl sulfate, naphthalenesulfonic acid orsulfosalicylic acid; quaternary ammonium salts with methyl bromide,methyl iodide or the like; salts with a halogen ion such as a bromineion, a chlorine ion or an iodine ion; salts with an alkali metal such aslithium, sodium or potassium; salts with an alkaline earth metal such ascalcium or magnesium; salts with a metal such as iron or zinc; saltswith ammonia; salts with an organic amine such as triethylenediamine,2-aminoethanol, 2,2-iminobis(ethanol),1-deoxy-1-(methylamino)-2-D-sorbitol,2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine orN,N-bis(phenyl-methyl)-1,2-ethanediamine; and the like.

In the case where there are geometrical isomers and/or optical isomersin the present compound of the present invention, these isomers are alsoincluded in the scope of the present invention.

Further, in the case where there is proton tautomerism in the presentcompound, the tautomeric isomers thereof (keto isomer, enol isomer) arealso included in the present invention.

In the case where there are hydrates and/or solvates in the presentcompound, these hydrates and/or solvates are also included in the scopeof the present invention.

In the case where there are crystalline polymorphisms and/or crystalpolymorphic group (crystal polymorphic system) in the present compound,the crystalline polymorphisms and/or crystal polymorphic group (crystalpolymorphic system) thereof are also included in the present invention.Here, crystal polymorphic group (crystal polymorphic system) meanscrystal forms at the respective stages in the case where the crystalform changes variously and/or its entirety, depending on the conditionsand/or the states (in this state, the formulated state is also included)such as manufacture thereof, crystallization, preservation or the like.

The present invention includes a pharmaceutically acceptable prodrug ofthe compound represented by the general formula (1) or a salt thereof.The pharma-ceutically acceptable prodrug is a compound having a groupwhich can be converted to an amino group, a hydroxyl group, a carboxylgroup or the like by solvolysis or under physiological conditions. Thegroup which forms the prodrug may be mentioned a group described in, forexample, Progress in Medicine, vol. 5, pp. 2157-2161, 1995 or“Development of Pharmaceuticals” (Hirokawa-Shoten, Limited, 1990) vol.7, Molecular design, pp. 163-198.

In addition, the present compound can also play a role as a prodrug withthe compound itself.

The “pharmaceutical composition” referred to in the present inventionmeans a composition utilizable as a medicine. The pharmaceuticalcomposition of the present invention may contain the present compound ora salt thereof and an additive(s) which is/are acceptable as a medicine(for example, an excipient, a binder, a disintegrant, a coating agent, astabilizer, a corrigent (a sweetener, a sour agent or a flavor or thelike), a tonicity agent, a buffer, a surfactant, a stabilizer, apreservative, a pH adjusting agent, a soothing agent), if necessary, byusing a necessary amount, and can be prepared.

The “glucocorticoid receptor agonist” referred to in the presentinvention means a compound having an agonist action by bonding to theglucocorticoid receptor. The agonist action may be either the completeagonist action or a partial agonist action and include, for example, anIL-6 production inhibitory action, a TNFα production inhibitory action,an IL-2 production inhibitory action, an IL-4 production inhibitoryaction, and an MCP-1 production inhibitory action.

The glucocorticoid receptor related diseases are not specificallylimited as it is a disease that can be prevented and/or treated with aglucocorticoid receptor agonist, and can be applied to a disease thatcan be usually prevented and/or treated with glucosteroids.

The “glucocorticoid receptor related disease” may be mentioned, forexample, endocrine diseases such as chronic adrenal corticalinsufficiency (primary, secondary, pituitary, iatrogenic), acute adrenalcortical insufficiency (adrenal crisis), adrenogenital syndrome,subacute thyroiditis, thyrotoxicosis [thyroid (toxic) crises], malignantexophthalmos accompanied by thyroid disease, isolated ACTH deficiency,idiopathic hypoglycemia or the like; collagen diseases such aserythematosus (systemic lupus and chronic discoid lupus), systemic lupus(including aortitis syndrome, Periarteritis nodosa, polyarteritis,Wegener's granulomatosis), polymyositis (dermatomyositis), scleroderma,or the like; kidney diseases such as nephrosis, nephrosis syndrome, orthe like; heart diseases such as congestive heart failure, or the like;allergic diseases such as bronchial asthma, asthmatic bronchitis(including infantile asthmatic bronchitis), allergy or intoxication bydrugs or other chemical substances (including drug rash, intoxicationdermatosis), serum sickness, or the like; blood diseases such as purpura(therombocytopenic and nonthrombocytopenic), aplastic anemia, leukemia(including acute leukemia, blastic crisis of chronic myelogenousleukemia, chronic lymphocytic leukemia, leukemia of skin), hemolyticanemia, agranulocytosis, or the like; digestive system diseases such asulcerative colitis, regional enteritis, improvement in systemicconditions of severe degenerative disease (including cancer last stage,sprue), or the like; liver diseases such as acute hepatitis, cholestaticacute hepatitis, chronic hepatitis, hepatic cirrhosis, or the like;pulmonary diseases such as sarcoidosis, diffuse interstitial pneumonia(including pulmonary fibrosis, irradiation pneumonitis), or the like;severe infectious diseases; tuberculosis disease such as pulmonarytuberculosis, tuberculous meningitis, tuberculous pleurisy, tuberculousperitonitis, tuberculous pericarditis, or the like; nervous disease suchas encephalo-myelitis (including encephalitis, myelitis), peripheralneuritis (including Guillain-Barre syndrome), myotonia congenita,myasthenia gravis, multiple sclerosis (including fasciculus opticusmyelitis), chorea minor, facial paralysis, spinal retinitis, or thelike; malignant tumor such as malignant lymphoma (lymphosarcomatosis,reticulosarcomatosis, Hodgkin's disease, cutaneous reticulosis, mycosisfungoides) and similar diseases (related diseases), eosinophilicgranuloma, recurrence and transition of breast cancer, or the like;digestive symptoms (nausea, vomiting) resulting from administration ofan anti-malignant tumor agent (cisplatin or the like); surgery relateddiseases such as adrenalectomy, surgical invasion of patients withadrenocortical insufficiency, pulmonary edema after invasion, organ ortissue transplantation, snake venom or insect venom (including severeinsect bite), fever of unknown origin, or the like; obstetrics andgynecology related diseases such as prevention of adhesion afterfallopian tube surgery, or the like; urology related diseases such asprostatic cancer, penile induration, or the like; skin diseases such aseczema and dermatitis group (acute eczema, subacute eczema, chroniceczema, contact dermatitis, nummular eczema, autosensitizationdermatitis, atopic dermatitis,-infantile eczema, lichen simplexchronicus Vidal, other neurodermatitis, seborrheic dermatitis,keratodermia tylodes palmaris progressiva, other dermatitis of hands andfingers, genital or anal eczema, auricular and ear canal eczema anddermatitis, nasal vestibule and nose wings peripheral eczema anddermatitis, or the like), prurigo group (including strophulus infantum,strophulus, urticaria perstans), urticaria, psoriasis and similardiseases (psoriasis vulgaris (serious cases), arthropathic psoriasis,psoriatic erythroderma, pustular psoriasis, acrodermatitis continuasuppurativa hallopeau, herpetiform impetigo, Reiter syndrome),palmoplantar pustulosis, lichen planus, scleredema adultorum, erythemagroup (erythema exudativum multiforme, erythema nodosum), anaphylactoidpurpura (simple type, Schonlein type, Henoch type), Weber Christiandisease, mucocutaneous ocular syndrome (ectodermosis erosivapluriorificialis, Stevens-Johnson disease, dermatostomatitis, Fuchssyndrome, Behcet's disease, Lipschutz' acute genital ulcer), Raynauddisease, alopecia areata, pemphigus group (pemphigus vulgaris, pemphigusfoliaceus, Senear-Usher syndrome, pemphigus vegetans), dermatitisherpetiformis (Duhring) (including pemphigoid, gestational herpes),hereditary bullous epidermolysis, herpes zoster, erythrodermia(including pityriasis rosea (Hebra)), lupus miliaris disseminatusfaciei, allergic vasculitis-Ruiter and similar diseases thereof(including parapsoriasis acuta), ulcerative chronic pyoderma, scleremaneonatorum, or the like; otolaryngology related diseases such as acuteor chronic otitis media, secretory otitis media or stenosis ofeustachian tube, Meniere disease and Meniere syndrome, acutesensorineural hearing loss, vasomotor (nervous) rhinitis, allergicrhinitis, pollinosis (hay fever), progressive gangrenous rhinitis,laryngitis or laryngeal edema, after-treatment after surgery in thefield of otorhinolaryngology, olfactory disturbance, acute or chronic(repetitive) sialadenitis, or the like; oral surgery related diseasessuch as intractable stomatitis and glossitis, or the like; glaucoma;rheumatic diseases such as rheumatic fever (including rheumaticcarditis), polymyalgia rheumatica, spondylarthritis ankylopoietica(rheumatoid spondylitis), or the like, further, and the followinginflammatory diseases, or the like.

The “inflammatory diseases” referred to in the present invention is notparticularly limited as long as it is a disease associated withinflammation.

For example, there may be mentioned inflammatory bone or joint diseases,ocular inflammatory diseases, asthma, bronchitis, rhinitis, dermatitis,inflammatory bowel disease or the like, preferably mentionedinflammatory bone or joint diseases and/or ocular inflammatory diseases.

Here, the “inflammatory bone or joint disease” is not particularlylimited as long as it is a disease accompanied by inflammation at thejoint portion, and examples thereof include, for example, rheumatoidarthritis, juvenile rheumatoid arthritis (including Still's disease),osteoarthritis, osteoporosis, spondylarthritis, or the like, preferablyrheumatoid arthritis and/or osteoarthritis.

In addition, the “ocular inflammatory diseases” is not particularlylimited as long as it is a disease accompanied by inflammation at eyepart, and examples thereof include anterior eye inflammatory diseasesand posterior eye inflammatory diseases.

The anterior eye inflammatory diseases include, for example, keratitis,keratoconjunctivitis, conjunctivitis, blepharitis, dry eye syndrome(hereinafter also referred to as “dry eye”), allergic conjunctivitis,uveitis, inflammation after anterior eye surgery, inflammation due torejection of ocular tissue transplantation, or the like, preferablykeratitis, keratoconjunctivitis, conjunctivitis, blepharitis, dry eyesyndrome (dry eye), allergic conjunctivitis, uveitis, and inflammationafter anterior eye surgery, particularly preferably keratitis,keratoconjunctivitis, conjunctivitis, dry eye syndrome (dry eye), andallergic conjunctivitis.

The posterior eye inflammatory diseases include age-related maculardegeneration, diabetic retinopathy, diabetic macular edema, neovascularmaculopathy, paroxysm epimacular membrane, proliferativevitreoretinopathy, pigmentary degeneration of the retina, centralretinal vein occlusion, central retinal artery occlusion, branch retinalvein occlusion, branch retinal artery occlusion, inflammation ordegeneration of posterior eye caused by retinal detachment or externalinjuries (including surgery of posterior eye), retinitis, uveitis,scleritis, optic neuritis, or the like, preferably retinal diseases suchas age-related macular degeneration, diabetic retinopathy, diabeticmacular edema, neovascular maculopathy, proliferative vitreoretinopathy,central retinal vein occlusion, central retinal artery occlusion, branchretinal vein occlusion, branch retinal artery occlusion, inflammation ordegeneration caused by external injuries (including surgery of posterioreye), retinitis, uveitis, scleritis, optic neuritis, or the like, andparticularly preferably age-related macular degeneration, diabeticmacular edema, central retinal vein occlusion, and branch retinal veinocclusion.

The “theraputic agent” referred to in the present invention means amedicine to be used for treating diseases. Also, the “prophylacticagent” referred to in the present invention means a medicine to be usedfor the prophylaxis of diseases.

(A) Preferred examples of the present compound include compounds inwhich the respective groups are groups as defined below and saltsthereof in the compounds represented by the general formula (1) andsalts thereof.

The compound or a salt thereof wherein, in the general formula (1),(a1) R¹ represents a hydrogen atom, a lower alkyl group, a carboxylgroup, an ester of a carboxyl group, an amide of a carboxyl group or acyano group;in the case where R¹ is a lower alkyl group, the lower alkyl group mayhave one or a plurality of groups selected from a halogen atom, a lowercycloalkyl group, an aryl group, a heterocyclic group, a hydroxyl group,an ester of a hydroxyl group, a lower alkoxyl group, a lower alkoxylgroup substituted by a halogen atom(s), a lower cycloalkyloxy group, anaryloxy group, a heterocyclicoxy group, an amino group, a loweralkylamino group, a lower cycloalkylamino group, an arylamino group, aheterocyclic amino group, an amide of an amino group, an amide of alower alkylamino group, an amide of a lower cycloalkylamino group, anamide of an arylamino group, an amide of a heterocyclic amino group, alower alkylcarbonyl group, a lower cycloalkylcarbonyl group, anarylcarbonyl group, a heterocyclic carbonyl group, a carboxyl group, anester of a carboxyl group, an amide of a carboxyl group and a cyanogroup as a substituent(s); and/or,(a2) R² represents a hydrogen atom, a lower alkylcarbonyl group, a lowercycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonylgroup, a carboxyl group, an ester of a carboxyl group, an amide of acarboxyl group, a phosphate group or an ester of a phosphate group;in the case where R² is a lower alkylcarbonyl group, a lowercycloalkylcarbonyl group, an arylcarbonyl group or a heterocycliccarbonyl group, the lower alkylcarbonyl group, the lowercycloalkylcarbonyl group, the arylcarbonyl group or the heterocycliccarbonyl group may have one or a plurality of groups selected from ahalogen atom, a lower cycloalkyl group, an aryl group, a heterocyclicgroup, a hydroxyl group, an ester of a hydroxyl group, a lower alkoxylgroup, a lower alkoxyl group substituted by a halogen atom(s), a lowercycloalkyloxy group, an aryloxy group, a heterocyclicoxy group, an aminogroup, a lower alkylamino group, a lower cycloalkylamino group, anarylamino group, a heterocyclic amino group, an amide of an amino group,an amide of a lower alkylamino group, an amide of a lowercycloalkylamino group, an amide of an arylamino group, an amide of aheterocyclic amino group, a lower alkylcarbonyl group, a lowercycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonylgroup, a carboxyl group, an ester of a carboxyl group, an amide of acarboxyl group and a cyano group as a substituent(s).That is, in the compound represented by the formula (1), a compound or asalt thereof comprising the respective combination of theabove-mentioned (a1) and (a2).(B) More preferred examples of the present compound include compounds inwhich the respective groups are groups as defined below and saltsthereof in the compounds represented by the general formula (1) andsalts thereof.The compound or a salt thereof wherein, in the general formula (1),(b1) R¹ represents a hydrogen atom, a lower alkyl group, a carboxylgroup or an ester of a carboxyl group;in the case where R¹ is a lower alkyl group, the lower alkyl group mayhave one or a plurality of groups selected from a halogen atom, ahydroxyl group, a lower alkoxyl group, a lower alkylcarbonyl group, acarboxyl group, an ester of a carboxyl group, an amide of a carboxylgroup and a cyano group as a substituent(s); and/or,(b2) R² represents a hydrogen atom, a lower alkylcarbonyl group, aheterocyclic carbonyl group, a phosphate group or an ester of aphosphate group; andin the case where R² is a lower alkylcarbonyl group, the loweralkylcarbonyl group may have one or a plurality of groups selected froma halogen atom, a hydroxyl group, an ester of a hydroxyl group, a loweralkoxyl group, a lower alkoxyl group substituted by a halogen atom(s),an amino group, a lower alkylamino group, a lower alkylcarbonyl group, acarboxyl group, an ester of a carboxyl group, an amide of a carboxylgroup and a cyano group as a substituent(s).That is, in the compound represented by the formula (1), a compound or asalt thereof comprising the respective combination of theabove-mentioned (b1) and (b2).(C) Further preferred examples of the present compound include compoundsin which the respective groups are groups as defined below, and saltsthereof in the compounds represented by the general formula (1) or saltsthereof.The compound or a salt thereof wherein, in the general formula (1),(c1) R¹ represents a hydrogen atom, a lower alkyl group or an ester of acarboxyl group; in the case where R¹ is a lower alkyl group, the loweralkyl group may have one or a plurality of groups selected from ahalogen atom, a hydroxyl group, a carboxyl group, an ester of a carboxylgroup, an amide of a carboxyl group and a cyano group as asubstituent(s); and/or(c2) R² represents a hydrogen atom, a lower alkylcarbonyl group, aheterocyclic carbonyl group or a phosphate group;in the case where R² is a lower alkylcarbonyl group, the loweralkylcarbonyl group may have one or a plurality of groups selected froma hydroxyl group, an amino group, a lower alkylamino group and acarboxyl group as a substituent(s).That is, in the compound represented by the formula (1), a compound or asalt thereof comprising the respective combination of theabove-mentioned (c1) and (c2).(D) Further preferred examples of the present compound include compoundsin which the respective groups are groups as defined below, and saltsthereof in the compounds represented by the general formula (1) or saltsthereof.The compound or a salt thereof wherein, in the general formula (1),(d1) R¹ represents a lower alkyl group; the lower alkyl group may haveone or a plurality of hydroxyl groups as a substituent(s); and/or,(d2) R² represents a hydrogen atom or a lower alkylcarbonyl group;in the case where R² is a lower alkylcarbonyl group, the loweralkylcarbonyl group may have one or a plurality of lower alkylaminogroups as a substituent(s).That is, in the compound represented by the formula (1), a compound or asalt thereof comprising the respective combination of theabove-mentioned (d1) and (d2).(E) Further preferred examples of the present compound include compoundsin which the respective groups are groups as defined below, and saltsthereof in the compounds represented by the general formula (1) or saltsthereof.The compound or a salt thereof wherein, in the general formula (1),(e1) R¹ represents methyl or 1-hydroxyethyl; and/or,(e2) R² represents a hydrogen atom or dimethylaminomethylcarbonyl.That is, in the compound represented by the formula (1), a compound or asalt thereof comprising the respective combination of theabove-mentioned (e1) and (e2).(F) Particularly preferred specific examples of the present compoundinclude the following compounds and salts thereof.

-   (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxy-3,3,3-trifluoropropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-7-[4-(2-ethoxycarbonyl-2-hydroxyethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxyacetoxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxyethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-7-[4-(3-cyano-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-(3-cyano-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-(3-fluoro-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-(3-ethoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-(3-t-butoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-(3,3-dimethyl-2-hydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-(3-carboxy-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-pyrrolidylcarbonyl)-2-hydroxy-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-morpholino)carbonyl-2-hydroxy-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-piperidino)carbonyl-2-hydroxy-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-[2-(N,N-dimethyl    aminoacetoxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[(2S)-[(2S)-pyrrolidylcarbonyloxy]-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (R)-7-[4-[2-(N,N-dimethylaminoacetoxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-(2-aminoacetoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-[(2S)-[(2S)-amino-3-methylbutanoyloxy]propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-[2-(3-carboxypropanoyloxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-[2-(2,3-dihydroxypropanoyl)oxypropyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   7-[4-[(2S)-[(2S)-amino-3-hydroxypropanoyloxy]propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-phosphonohydroxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-phosphonohydroxybutyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,-   (S)-7-[4-(3-cyano-2-phosphonohydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

The producing method of the present compound can be roughly classifiedby the methods shown below, and the method can be optionally selecteddepending on the kind of the substituents. In addition, with regard tothe respective specific producing methods, these are explained in detailin the item of Production Examples in Examples mentioned later. Theseexamples are intended to make the present invention more clearlyunderstandable, and do not limit the scope of the present invention.“PG” used in the following Synthetic Routes means a protective group and“LG” a leaving group.

The present compound (I)-(a) (the compound that R² is a hydrogen atom inthe general formula (1).) can be produced according to SyntheticRoute 1. Namely, the present compound (I)-(a) can be given by thereaction of the compound (A) (produced with reference to theabove-mentioned Patent Document 2.) with the compound (II) or thecompound (III) in an organic solvent such as ethanol andN,N-dimethylformamide (hereinafter also referred to as “DMF”.) in thepresence of a base such as potassium carbonate and cesium carbonate at0° C. to 120° C. for 1 hour to 24 hours. Or else, the compound (VI) canbe given by the reaction of the compound (A) and the compound (IV) underthe same conditions as mentioned above, or of the compound (A) with thecompound (V) in an organic solvent such as tetrahydrofuran (hereinafteralso referred to as “THF”.) and methylene chloride in the presence oftributylphosphine and 1,1′-(azodicarbonyl)dipiperidine at 0° C. to 80°C. for 1 hour to 24 hours. The present compound (I)-(a) can be given bythe reaction of the obtained compound (VI) under general deprotectionconditions of a hydroxyl group, i.e., in an organic solvent such asmethanol in the presence of an acid or a base, or under catalytichydrogenation conditions at 0° C. to 100° C. for 1 hour to 24 hours.

Synthetic Route 1

Also, the present compound (I)-(a) (the compound in which R² is ahydrogen atom in the general formula (1).) can be produced according toSynthetic Route 2. Namely, the compound (VIII) can be given by thereaction of the compound (A) and the compound (VII) in an organicsolvent such as ethanol and DMF in the presence of a base such aspotassium carbonate and cesium carbonate at 0° C. to 120° C. for 1 hourto 24 hours. Further, the present compound (I)-(a) can be given by thereaction of the obtained compound (VIII) and a reducing agent such assodium borohydride and lithium aluminum hydride in an organic solventsuch as methanol and methylene chloride at 0° C. to 50° C. for 30minutes to 24 hours.

Synthetic Route 2

The present compound (I)-(b) (the compound that R¹ is a lower alkylgroup which may have a substituent(s), and R² is a hydrogen atom in thegeneral formula (1).) can be produced according to Synthetic Route 3.Namely, the compound (X) can be given by the reaction of the compound(A) and the compound (IX) in an organic solvent such as ethanol and DMFin the presence of a base such as potassium carbonate and cesiumcarbonate at 0° C. to 120° C. for 1 hour to 24 hours. Further, thepresent compound (I)-(b) can be given by the reaction of can be given bythe reaction of the obtained compound (X) and a nucleophilic reagent inan organic solvent such as DMF and methylene chloride at 0° C. to 100°C. for 1 hour to 24 hours.

Synthetic Route 3

The present compound (I)-(c) (the compound that R¹ is a lower alkylgroup having a hydroxyl group, and R² is a hydrogen atom in the generalformula (1). Also, n in Synthetic Route 4 represents an integer of 1 ormore.) can be produced according to Synthetic Route 4. Namely, thepresent compound (I)-(c) can be given by the reaction of can be given bythe reaction of the compound (XIII)-(a) or the compound (XIII)-(b) whichcan be given by the reaction of the compound (A) with the compound (XI)or the compound (XII) in an organic solvent such as ethanol and DMF inthe presence of a base such as potassium carbonate and cesium carbonateat 0° C. to 120° C. for 1 hour to 24 hours, under general deprotectionconditions of a hydroxyl group, i.e., in an organic solvent such asmethanol in the presence of an acid or a base, or under catalytichydrogenation conditions at 0° C. to 100° C. for 1 hour to 24 hours.

Synthetic Route 4

The compound (XI) (n represents an integer of 1 or more) can be producedaccording to Synthetic Route 5. Namely, the compound (XV) (the compoundthat LG is a mesyl group or a tosyl group) can be given by the reactionof the compound (XIV) with methanesulfonyl chloride, orp-toluenesulfonyl chloride in an organic solvent such as methylenechloride in the presence of a base such as pyridine and 2,6-lutidine,etc. at −40° C. to room temperature for 30 minutes to 24 hours. Further,the compound (XI) can be given by the reaction of the obtained compound(XV) in an organic solvent such as methanol in the presence of a basesuch as potassium carbonate at room temperature to 80° C. for 30 minutesto 6 hours.

Synthetic Route 5

The present compound (I)-(d) (the compound that R¹ is —CH₂COOR^(m), andR² is a hydrogen atom in the general formula (1). R^(m) represents alower alkyl group.), the present compound (I)-(e) (the compound that R¹is —CH₂COOH, and R² is a hydrogen atom in the general formula (1).) andthe present compound (I)-(f) (the compound that R¹ is —CH₂—R, and R² isa hydrogen atom in the general formula (1). R^(n) represents an ester ofa carboxyl group —COOR^(f) or an amide of a carboxyl group—CONR^(g)R^(h). R^(f), R^(g) and R^(h) are the same as mentioned above.)can be produced according to Synthetic Route 6. Namely, the compound(XVII) can be given by the reaction of the compound (A) with methylbromoacetate (XVI) in an organic solvent such as acetonitrile and DMF inthe presence of a base such as potassium carbonate and cesium carbonateat 0° C. to 120° C. for 1 hour to 24 hours. Further, the presentcompound (I)-(d) can be given by the reaction of the obtained compound(XVII) with an acetic acid ester (XVIII) (R^(m) are the same asmentioned above.) in an organic solvent such as diethyl ether and THF inthe presence of a base such as sodium hydride and lithiumdiisopropylamide at −80° C. to 0° C. for 15 minutes to 8 hours, andthen, by the reaction with a reducing agent such as sodium borohydrideand lithium aluminum hydride in an organic solvent such as methanol andmethylene chloride at 0° C. to 50° C. for 30 minutes to 24 hours.

In addition, the present compound (I)-(e) can be given by the reactionof the compound (I)-(d) in an organic solvent such as methanol andethanol in the presence of a base such as sodium hydroxide at 0° C. to80° C. for 30 minutes to 24 hours.

Further, the present compound (I)-(f) can be given by the reaction ofthe compound (I)-(e) with an alcohol (XIX) or an amine (XX) in anorganic solvent such as THF and DMF in the presence of a condensingagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (hereinafter also referred to as “EDC”) andO-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (hereinafter also referred to as “HATU”) and a basesuch as 4-dimethylaminopyridine and triethylamine at 0° C. to 80° C. for1 hour to 24 hours.

Synthetic Route 6

The present compound (I)-(g) (the compound that R² is a loweralkylcarbonyl group which may have a substituent(s), a lowercycloalkylcarbonyl group which may have a 5 substituent(s), anarylcarbonyl group which may have a substituent(s) or a heterocycliccarbonyl group which may have a substituent(s) in the general formula(1).) can be produced according to Synthetic Route 7. Namely, thepresent compound (I)-(g) can be given by the reaction of the presentcompound (I)-(a) with carboxylic acid (XXI) in an organic solvent suchas THF and DMF in the presence of a condensing agent such as EDC andHATU, and a base such as 4-dimethylaminopyridine and triethylamine at 0°C. to 80° C. for 1 hour to 24 hours, or of the present compound (I)-(a)with an acid anhydride (XXI) in an organic solvent such as THF andpyridine in the presence of a base such as 4-dimethylaminopyridine at 0°C. to 80° C. for 1 hour to 24 hours.

Synthetic Route 7

The present compound (I)-(h) (the compound that R² is a phosphate groupin the general formula (1).) can be produced according to SyntheticRoute 8. Namely, the present compound (I)-(i) (the compound that R² isan ester of a phosphate group —PO(OR)₂ in the general formula (1).) canbe given by the reaction of the present compound (I)-(a) withdialkoxy(diisopropylamino)phosphine (XXIII) (R represents a lower alkylgroup.) in an organic solvent such as DMF in the presence of1H-tetrazole and m-chlorobenzoic acid at 0° C. to 50° C. for 10 minutesto 3 hours. Further, the present compound (I)-(h) can be given by thereaction of the obtained present compound (I)-(i) with trifluoroaceticacid in an organic solvent such as methylene chloride at 0° C. to 50° C.for 10 minutes to 3 hours.

Synthetic Route 8

The compounds of the present invention produced by the Synthetic Routesdescribed above can be also in the form of a salt, a hydrate or asolvate as described above, using commonly used techniques.

In order to find the usefulness of the present compound as a medicine,Pharmacological Tests mentioned later were carried out. Incidentally, itwas confirmed that the present compound is particularly useful as amedicine by carrying out the same assay for the compound conventionallyknown from the literature and comparing it with the test results of thepresent compound.

By using the glucocorticoid receptor (hereinafter also referred to as“GR”.) competitive assay kit, GR competitive assay by fluorescencepolarization was carried out. As a result, the present compounds showedexcellent GR binding activity.

Also, an IL-6 production inhibitory action in a human corneal epitheliumcell line after stimulation by lipopolysaccharide (hereinafter alsoreferred to as “LPS”.) was investigated. As a result, the presentcompounds showed an excellent IL-6 production inhibitory action, i.e.,an action as a GR agonist.

Further, a TNFα production inhibitory action in rat whole blood afterstimulation by LPS was investigated. As a result, the present compoundsshowed an excellent TNFα production inhibitory action, i.e., an actionas a GR agonist.

Moreover, an IL-2 production inhibitory action in a normal human CD4⁺ Tcell after stimulation by an anti-CD3/CD28 antibody was investigated. Asa result, the present compounds showed an excellent IL-2 productioninhibitory action, i.e., an action as a GR agonist.

Furthermore, an IL-4 production inhibitory action in a normal human CD4+T cell after stimulation by an anti-CD3/CD28 antibody was investigated.As a result, the present compounds showed an excellent IL-4 productioninhibitory action, i.e., an action as a GR agonist.

Also, an MCP-1 production inhibitory action in a human monocyte cellafter stimulation by LPS was investigated. As a result, the presentcompounds showed an excellent MCP-1 production inhibitory action, i.e.,an action as a GR agonist.

From the above, the present compounds have a production inhibitoryaction of a plurality of cytokines, i.e., the above-mentioned IL-6,TNFα, IL-2, IL-4 and MCP-1, so that, in particular, these are useful asa GR agonist, and confirmed that these are useful as a prophylactic ortherapeutic agent for diseases to which a GR agonist such as steroidsare effective, in particular, for inflammatory diseases (bone and jointdiseases, ocular inflammatory diseases, or the like). In addition, thepresent compounds are further useful as a GR agonist since, for example,these have a production inhibitory action to a number of cytokines ascompared with the conventionally known compounds as disclosed in PatentDocument 2.

In addition, in order to evaluate the possibility of the presentcompounds for a treatment agent of anterior eye inflammatory diseases,an inhibitory effect of the present compounds on edema formation in acarrageenin-caused conjunctivitis model of a rat, an inhibitory effectof the present compounds on a number of infiltrated cells into aqueoushumor in an anterior chamber tap ocular inflammation model of a rabbit,a treatment effect of the present compounds on corneal disorder inexorbital lachrymal gland-extracted dry eye model of a rat and aninhibitory effect of the present compounds on hyperemia in ovalbuminactively sensitized allergic conjunctivitis model of a rabbit wereinvestigated. As a result, the present compounds showed an edemaformation inhibitory effect, a number of infiltrated cells into aqueoushumor inhibitory effect, a corneal disorder treatment effect and ahyperemia inhibitory effect.

Accordingly, the present compound is confirmed to be useful as ananterior eye inflammatory diseases treatment agent, in particular, as aprophylactic or therapeutic agent for keratitis, keratoconjunctivitis,conjunctivitis, blepharitis, dry eye syndrome (dry eye), allergicconjunctivitis, uveitis, inflammation after surgery and inflammation dueto rejection of ocular tissue transplantation, or the like, morepreferably as a prophylactic or therapeutic agent for the ocularinflammatory diseases such as keratitis, keratoconjunc-tivitis,conjunctivitis, dry eye syndrome (dry eye), allergic conjunctivitis,uveitis, inflammation after surgery, or the like.

Further, in order to evaluate the possibility of the present compoundsas a treatment agent for posterior eye inflammatory diseases, aninhibitory effect of the present compounds on a leaked amount of thefluorescent dye into a vitreous body in a VEGF-induced retinal elevatedvascular permeability model of a rabbit was investigated. As a result,the present compounds showed a retinal elevated vascular permeabilityinhibitory action.

Accordingly, the present compound is confirmed to be useful as anposterior eye inflammatory diseases treatment agent, in particular, as aprophylactic or therapeutic agent for age-related macular degeneration,diabetic retinopathy, diabetic macular edema, neovascular maculopathy,proliferative vitreoretinopathy, central retinal vein occlusion, centralretinal artery occlusion, branch retinal vein occlusion, branch retinalartery occlusion, inflammation or degeneration of posterior eye causedby external injury, retinitis, uveitis, scleritis, optic neuritis, orthe like, more preferably as a prophylactic or therapeutic agent for theocular inflammatory diseases such as age-related macular degeneration,diabetic macular edema, central retinal vein occlusion, branch retinalvein occlusion, or the like.

In addition, during the above-mentioned Pharmacological Test was carriedout, no serious adverse side effect due to administration of the presentcompound was observed, and it was confirmed that it is useful as aprophylactic or therapeutic agent for ocular inflammatory diseases.

A detailed explanation of this matter will be more specificallydescribed in the section of “Pharmacological Test” in Examples describedbelow.

The present compound can be administered either orally or parenterally.The administration form may include oral administration, localadministration to eyes (instillation administration, administration intothe interior of the conjunctival sac, administration into the vitreousbody, subconjunctival administration, subtenon administration, or thelike), intravenous administration, intramuscular administration,intraarticular administration, pernasality administration, inhalationadministration, percutaneous administration, or the like. It ispreferably a parenteral administration form, and may include localadministration to eyes (instillation administration, administration intothe interior of the conjunctival sac, administration into the vitreousbody, subconjunctival administration, subtenon administration, or thelike), intravenous administration, intramuscular administration,intraarticular administration, pernasality administration, inhalationadministration, percutaneous administration, or the like. It isparticularly preferably local administration to eyes (instillationadministration, administration into the interior of the conjunctivalsac, administration into the vitreous body, subconjunctivaladministration, subtenon administration, or the like).

Examples of the dosage form of the present compound include a tablet, acapsule, a granule, a powder, an enteric tablet, an injection, an eyedrop, a suppository, a percutaneous absorbent, an ointment, aerosols(including an inhalant) and the like. Such a preparation can be preparedusing a commonly used technique. A preferable dosage form to be usedwhen it is local administered to eyes may include an ophthalmic agent,in particular, as a prophylactic or therapeutic agent for a dissolutiontype ophthalmic agent, a suspension type ophthalmic agent, an emulsiontype ophthalmic agent or a gel type ophthalmic agent, or the like, anophthalmic ointment, in particular, a coating agent for the interior ofthe conjunctival sac or a coating agent for eyelid, or the like, or aninjection, in particular, a subconjunctival administration agent, aTenon capsule administration agent or an administration agent into thevitreous body, or the like.

For example, an oral preparation such as a tablet, a capsule, a granuleor a powder can be prepared by optionally adding a necessary amount ofan excipient such as lactose, mannitol, starch, crystalline cellulose,light silicic anhydride, calcium carbonate or calcium hydrogenphosphate; a lubricant such as stearic acid, magnesium stearate or talc;a binder such as starch, hydroxypropyl cellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone; a disintegrant such as carboxymethylcellulose, low-substituted hydroxypropylmethyl cellulose or calciumcitrate; a coating agent such as hydroxypropylmethyl cellulose, macrogolor a silicone resin; a stabilizer such as ethyl p-hydroxybenzoate orbenzyl alcohol; a corrigent such as a sweetener, a sour agent or aflavor, or the like.

A parenteral preparation such as an injection or an eye drop can beprepared by optionally adding a necessary amount of a tonicity agentsuch as sodium chloride, concentrated glycerin, propylene glycol,polyethylene glycol, potassium chloride, sorbitol or mannitol; a buffersuch as sodium phosphate, sodium hydrogen phosphate, sodium acetate,citric acid, glacial acetic acid or trometamol; a surfactant such asPolysorbate 80, polyoxy 40 stearate or polyoxyethylene hydrogenatedcastor oil 60; a stabilizer such as sodium citrate or sodium edetate; apreservative such as benzalkonium chloride, paraben, benzothoniumchloride, p-hydroxybenzoate ester, sodium benzoate or chlorobutanol; apH adjusting agent such as hydrochloric acid, citric acid, phosphoricacid, glacial acetic acid, sodium hydroxide, sodium carbonate or sodiumhydrogen carbonate; a soothing agent such as benzyl alcohol, or thelike.

The dose of the present compound can be appropriately selected dependingon the symptoms, age, dosage form or the like. For example, in the caseof an oral preparation, it can be administered in an amount of generally0.01 to 1,000 mg, preferably 1 to 100 mg per day in a single dose orseveral divided doses. Further, in the case of an eye drop, apreparation comprising the present compound at a concentration ofgenerally 0.0001% to 10% (w/v), preferably 0.01% to 5% (w/v) can beadministered in a single dose or several divided doses.

Hereinafter, Production Examples of the present compound, PreparationExamples and results of Pharmacological Test will be described. However,these examples are described for the purpose of understanding thepresent invention better and are not meant to limit the scope of thepresent invention.

PRODUCTION EXAMPLES Reference Example 1 (S)-4-benzyloxy-2-hydroxybutylmethanesulfonate (the Reference Compound 1-1)

A methylene chloride (50 mL) solution of methanesulfonyl chloride (4.1mL, 53.0 mmol) was added dropwise to a methylene chloride (200 mL)solution of (S)-4-benzyloxy-1,2-butanediol (10.0 g, 51.0 mmol) and2,6-lutidine (59 mL, 507 mmol) at −20° C. over 30 minutes, and themixture was stirred at room temperature for 24 hours. Further, amethylene chloride (30 mL) solution of methanesulfonyl chloride (1.3 mL,16.8 mmol) was added dropwise to the above mixture at room temperatureover 30 minutes, and the mixture was stirred for 1.5 hours. The mixturewas washed with 0.5N hydrochloric acid (200 mL×4), a saturated aqueoussodium hydrogen carbonate solution (100 mL×3), and a saturated salinesolution (100 mL). The organic layer was dried over anhydrous magnesiumsulfate and filtered. The filtrate was concentrated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (chloroform/methanol) to give the titled referencecompound (12.3 g) (Yield: 88%).

TABLE 1 Reference compound 1-1 ¹H-NMR (400 MHz, CDCl₃) δ 7.39-7.28 (5H,m), 4.53 (2H, s), 40.30-4.07

(3H, m), 3.80-3.62 (2H, m), 3.20 (1H, d, J = 2.9 Hz), 3.05 (3H, s),1.93-1.76 (2H, m)

Reference Example 2 (S)-4-benzyloxy-1,2-epoxybutane (the ReferenceCompound 2-1)

A mixture of (S)-4-benzyloxy-2-hydroxybutyl methanesulfonate (thereference compound 1-1, 12.3 g, 44.8 mmol), potassium carbonate (12.3 g,89.0 mmol) and methanol (100 mL) was stirred at room temperature for 75minutes. After removing the solvent under reduced pressure, 0.5N sodiumhydroxide (450 mL) and ethyl acetate (200 mL) were added to the residue.The mixture was distributed, and the aqueous layer was extracted withethyl acetate (100 mL×2). The organic layers were combined, and washedwith a saturated saline solution (100 mL). The organic layer was driedover anhydrous magnesium sulfate and filtered. The filtrate wasconcentrated under reduced pressure to give the titled referencecompound (8.0 g) (quantitative).

TABLE 2 Reference compound 2-1 ¹H-NMR (400 MHz, CDCl₃) δ 7.41-7.27 (5H,m), 4.53 (2H, s),

3.69-3.58 (2H, m), 3.12-3.04 (1H, m), 2.79 (1H, dd, J = 5.1, 4.0 Hz),2.53 (1H, dd, J = 5.1, 2.7 Hz), 1.98-1.86 (1H, m),1.84-1.72 (1H, m)

(R)-4-benzyloxy-1,2-epoxybutane (the Reference Compound 2-2)

Under ice-cooling, p-toluenesulfonyl chloride (1.45 g, 7.6 mmol) wasadded to a pyridine (25 mL) solution of (R)-4-benzyloxy-1,2-butanediol(1.24 g, 6.3 mmol) and after stirring for 5 hours, the mixture wasstirred at room temperature overnight. The mixture was diluted withethyl acetate (100 mL), and washed with 1N hydrochloric acid (50 mL, 30mL) and a saturated saline solution (50 mL). The organic layer was driedover anhydrous magnesium sulfate and filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was dissolvedin tetrahydrofuran (60 mL), sodium hydride (0.38 g, 9.5 mmol) was addedthereto at room temperature, and the resulting mixture was stirred at50° C. overnight. After allowing to cool at room temperature, water (200mL) was added to the mixture and the mixture was extracted with ethylacetate (200 mL), and the organic layer was washed with a saturatedsaline solution (100 mL). The organic layer was dried over anhydrousmagnesium sulfate and filtered, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the titled referencecompound (0.99 g) (Yield: 89%).

TABLE 3 Reference compound 2-2 ¹H-NMR (400 MHz, CDCl₃) δ 7.38-7.27 (5H,m), 4.53 (2H, s),

3.69-3.57 (2H, m), 3.12-3.03 (1H, m), 2.79 (1H, dd, J = 4.9, 4.0 Hz),2.53 (1H, dd, J = 4.9, 2.7 Hz), 1.98-1.87 (1H, m), 1.84-1.73 (1H, m)

Reference Example 3(S)-7-[4-(4-benzyloxy-2-hydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Reference Compound 3-1)

A mixture of8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound A (produced with reference to the above-mentioned PatentDocument 2, hereinafter the same), 500 mg, 1.11 mmol),(S)-4-benzyloxy-1,2-epoxybutane (the reference compound 2-1, 500 mg,2.81 mmol), potassium carbonate (600 mg, 4.34 mmol) and ethanol (5 mL)was stirred at 60° C. for 7 hours. To the mixture was added water (30mL), and the mixture was extracted with ethyl acetate (30 mL×2). Theorganic layer was washed with a saturated saline solution (30 mL), driedover anhydrous magnesium sulfate and filtered. The filtrate wasconcentrated under reduced pressure and the obtained residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the titled reference compound (420 mg) as white amorphous (Yield:60%).

TABLE 4 Reference compound 3-1 ¹H-NMR (400 MHz, CDCl₃) δ 7.39-7.28 (5H,m), 7.21 (1H, dd, J =

6.6, 2.2 Hz), 6.92-6.84 (2H, m), 6.70 (1H, d, J = 7.8 Hz), 6.61-6.54(2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.56 (2H, s),4.30-4.21 (1H, m), 4.04-3.95 (2H, m) , 3.79 (3H, s), 3.79-3.66 (2H, m),3.46 (3H, s), 3.08 (1H, t, J = 3.0 Hz), 2.01 (3H, s), 1.99-1.92 (2H, m),1.54-1.50 (1H, m), 1.28 (3H, s), 0.90 (3H, s)

Reference Example 48-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-tetrahydropyran-2-yloxyethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Reference Compound 4-1)

A tetrahydrofuran (5 mL) suspension of8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound A, 100 mg, 0.22 mmol), 2-(tetrahydropyran-2-yloxy)ethanol(65 μL, 0.48 mmol), tri-n-butylphosphine (115 μL, 0.48 mmol) and1,1′-(azodicarbonyl)dipiperidine (115 mg, 0.46 mmol) was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (30mL), and the organic layer was washed with a saturated saline solution(30 mL×2). The organic layer was dried over anhydrous magnesium sulfate,and filtered. The filtrate was concentrated under reduced pressure andthe obtained residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the titled reference compound (150 mg) asa yellow oily product (quantitative).

TABLE 5 Reference compound 4-1 1H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J= 8.8 Hz), 6.88 (2H, d,

J = 8.0 Hz), 6.70 (1H, d, J = 8.0 Hz), 6.64-6.59 (2H, m), 6.38 (1H, td,J = 8.4, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.22 (1H, d, J = 13.9 Hz), 4.85 (1H, d, J = 13.9 Hz), 4.26-4.18 (2H, m), 4.14-4.05 (1H, m),3.98-3.82 (2H, m), 3.80 (3H, s), 3.79-3.63 (2H, m), 3.47 (3H, s),2.84-2.79 (1H, m), 2.01 (3H, s), 1.91-1.48 (6H, m), 1.28 (3H, s), 0.89(3H, s)

Reference Example 57-[4-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Reference Compound 5-1)

A mixture of8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound A, 600 mg, 1.3 mmol), p-toluenesulfonic acid(2,2-dimethyl-1,3-dioxolan-4-yl)methyl ester (572 mg, 2.0 mmol), cesiumcarbonate (868 mg, 2.7 mmol) and N,N-dimethylformamide (5.0 mL) wasstirred at 80° C. overnight. After allowing to cool at room temperature,water (150 mL) was added to the mixture and the mixture was extractedwith ethyl acetate (150 mL). The organic layer was washed with asaturated saline solution (150 mL), dried over anhydrous magnesiumsulfate and filtered. The filtrate was concentrated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the titled referencecompound (710 mg) as white amorphous (Yield: 95%).

TABLE 6 Reference compound 5-1 ¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J= 8.5 Hz), 6.93-6.84 (2H,

m), 6.70 (1H, d, J = 8. 0 Hz), 6.63-6.55 (2H, m), 6.38 (1H, td, J = 8.3,2.4 Hz), 6.04 (1H, dd, J = 11.3, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz),4.84 (1H, d, J = 13.7 Hz), 4.57-4.47 (1H, m), 4.20 (1H, dd, J = 8.5, 6.3Hz), 4.11 (1H, dd, J = 9.5, 5.6 Hz), 4.01 (1H, dd, J = 9.5, 5.9 Hz),3.93 (1H, dd, J = 8.5, 5.9 Hz), 3.80 (3H, s), 3.68 (1H, s), 3.46 (3H,s), 2.01 (3H, s), 1.49 (3H, s), 1.42 (3H, s), 1.28 (3H, s), 0.91 (3H, s)

Reference compounds 5-2 to 5-6 were obtained by using the compound A anda commercially available compound in accordance with the productionprocess of Reference compound 5-1.

(R)-7-[4-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Reference Compound 5-2)

TABLE 7

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 8.3 Hz), 6.92-6.84 (2H, m),6.70 (1H, d, J = 8.0 Hz), 6.63-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.3Hz), 6.04 (1H, dd, J = 11.3, 2.3 Hz), 5.21 (1H, d, J = 13.4 Hz), 4.84(1H, d, J = 13.4 Hz), 4.57-4.47 (1H, m), 4.20 (1H, dd, J = 8.7, 6.5 Hz),4.11 (1H, dd, J = 9.4, 5.7 Hz), 4.01 (1H, dd, J = 9.4, 5.7 Hz), 3.93(1H, dd, J = 8.4, 5.7 Hz), 3.80 (3H, s), 3.68 (1H, s), 3.46 (3H, s),2.01 (3H, s), 1.49 (3H, s), 1.42 (3H, s), 1.28 (3H, s), 0.91 (3H, s)

(S)-7-[4-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Reference Compound 5-3)

TABLE 8

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 8.5 Hz), 6.93-6.85 (2H, m),6.70 (1H, d, J = 8.1 Hz), 6.63-6.55 (2H, m), 6.38 (1H, td, J = 8.3, 2.4Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84(1H, d, J = 13.7 Hz), 4.57-4.47 (1H, m), 4.20 (1H, dd, J = 8.5, 6.3 Hz),4.13-4.09 (1H, m), 4.01 (1H, dd, J = 9.4, 5.7 Hz), 3.93 (1H, dd, J =8.4, 5.7 Hz), 3.80 (3H, s), 3.68 (1H, s), 3.46 (3H, s), 2.01 (3H, s),1.49 (3H, s), 1.42 (3H, s), 1.28 (3H, s), 0.91 (3H, s)

(R)-7-[4-(2,3-epoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Reference Compound 5-4)

TABLE 9

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 8.0 Hz), 6.93-6.84 (2H, m),6.70 (1H, d, J = 8.0 Hz), 6.65-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.4Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84(1H, d, J = 13.7 Hz), 4.30 (1H, dd, J = 11.1, 3.0 Hz), 4.06-3.97 (1H,m), 3.81 (3H, s), 3.68 (1H, s), 3.46 (3H, s), 3.42-3.36 (1H, m), 2.94(1H, t, J = 4.5 Hz), 2.83-2.76 (1H, m), 2.01 (3H, s), 1.28 (3H, s), 0.91(3H, s)

(S)-7-[4-(2,3-epoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Reference Compound 5-5)

TABLE 10

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 8.3 Hz), 6.93-6.84 (2H, m),6.70 (1H, d, J = 8.0 Hz), 6.64-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.4Hz), 6.04 (1H, dd, J = 11.3, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84(1H, d, J = 13.7 Hz), 4.30 (1H, dd, J = 11.1, 3.0 Hz), 4.07-3.96 (1H,m), 3.81 (3H, s), 3.68 (1H, s), 3.46 (3H, s), 3.43-3.35 (1H, m), 2.94(1H, t, J = 4.5 Hz), 2.84-2.76 (1H, m), 2.01 (3H, s), 1.28 (3H, s), 0.91(3H, s)

7-[4-(3,3-dimethyl-2-oxobutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Reference Compound 5-6)

TABLE 11

¹H-NMR (400 MHz, CDCl₃) δ 7.20 (1H, d, J = 8.3 Hz), 6.93-6.83 (2H, m),6.70 (1H, d, J = 8.0 Hz), 6.64 (1H, d, J = 2.4 Hz), 6.47 (1H, dd, J =8.3, 2.4 Hz), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.03 (1H, dd, J = 11.5,2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.93 (2H, s), 4.84 (1H, d, J = 13.7Hz), 3.80 (3H, s), 3.69 (1H, s), 3.46 (3H, s), 2.01 (3H, s), 1.28 (12H,s), 0.89 (3H, s)

Reference Example 68-(5-fluoro-2-methylphenoxymethyl)-7-[4-(methoxycarbonylmethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Reference Compound 6-1)

A mixture of8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxy-phenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound A, 2.0 g, 4.4 mmol), methyl bromoacetate (0.64 mL, 6.8mmol), potassium carbonate (0.95 g, 6.9 mmol) and dehydratedacetonitrile (45 mL) was refluxed at 100° C. overnight. After allowingto cool at room temperature, water (100 mL) was added to the mixture andthe mixture was extracted with ethyl acetate (100 mL). The organic layerwas washed with a saturated saline solution (100 mL) and concentratedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (hexane/ethyl acetate) to give the titledreference compound (2.4 g) as pale orange amorphous (quantitative).

TABLE 12

¹H-NMR (400 MHz, DMSO-d₆) δ 7.17 (1H, d, J = 8.3 Hz), 6.99 (1H, t, J =7.6 Hz), 6.78 (2H, s), 6.71 (1H, d, J = 2.4 Hz), 6.61 (1H, dd, J = 8.3,2.4 Hz), 6.48 (1H, td, J = 8.3, 2.4 Hz), 6.12-6.03 (2H, m), 5.22 (1H, d,J = 14.1 Hz), 4.86 (2H, s), 4.82 (1H, d, J = 14.1 Hz), 3.79 (3H, s),3.72 (3H, s), 3.32 (3H, s), 1.92 (3H, s), 1.07 (3H, s), 0.75 (3H, s)

Reference Example 7 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (theReference Compound 7-1)

Under ice-cooling, an aqueous (30 mL) solution of potassium permanganate(1.8 g, 11.3 mmol) was added dropwise to an aqueous (50 mL) solution of2,2-dimethyl-1,3-dioxolane-4-methanol (1.0 g, 7.6 mmol) and potassiumhydroxide (1.0 g, 15 mmol), and the mixture was stirred for 2 hours. Themixture was filtered on celite, and the filtrate was concentrated underreduced pressure. A saturated aqueous potassium hydrogen sulfatesolution was added to the resulting filtrate until a pH thereof became4. The mixture was extracted with ethyl acetate (200 mL×2), and theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure to give the titledreference compound (0.33 g) as a colorless oily product (Yield: 30%).

TABLE 13

¹H-NMR (500 MHz, CDCl₃) δ 4.62 (1H, dd, J = 7.6, 4.8 Hz), 4.31 (1H, dd,J = 8.9, 7.6 Hz), 4.20 (1H, dd, J = 8.9, 4.8 Hz), 1.54 (3H, s), 1.42(3H, s)

The reference compound 7-2 was obtained by using a commerciallyavailable compound in accordance with the production process of thereference compound 7-1.

(S)-(−)-N-t-butylcarbonyl-2,2-dimethyl-1,3-dioxazolidine-4-carboxylicacid (the reference compound 7-2)

TABLE 14

¹H-NMR (400 MHz, CDCl₃) δ 4.54-4.04 (3H, m), 1.52 (12H, s), 1.43 (3H, s)

Reference Example 8(S)-7-[4-(2-benzyloxyacetoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Reference Compound 8-1)

A mixture of(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound 1-1, 60 mg, 0.12 mmol), benzyloxyacetic acid (4 mg, 0.24mmol), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (45mg, 0.24 mmol), 4-dimethylamino-pyridine (2.9 mg, 0.024 mmol) andanhydrous methylene chloride (3.0 mL) was stirred at room temperatureovernight. Water (10 mL) was added to the mixture and the resultingmixture was extracted with ethyl acetate (10 mL×2). The organic layerwas washed with a saturated saline solution (10 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure and the obtained residue was purified by silicagel column chromatography (hexane/ethyl acetate) to give the titledreference compound (62 mg) as a white solid (Yield: 81%).

TABLE 15

¹H-NMR (400 MHz, CDCl₃) δ 7.41-7.27 (5H, m), 7.22 (1H, d, J = 8.8 Hz),6.93-6.82 (2H, m), 6.70 (1H, d, J = 8.1 Hz), 6.60-6.53 (2H, m), 6.38(1H, td, J = 8.4, 2.5 Hz), 6.03 (1H, dd, J = 11.2, 2.4 Hz), 5.47-5.37(1H, m), 5.21 (1H, d, J = 13.7 Hz), 4.83 (1H, d, J = 13.7 Hz), 4.65 (2H,s), 4.17-4.01 (4H, m), 3.79 (3H, s), 3.46 (3H, s), 2.01 (3H, s), 1.43(3H, d, J = 6.3 Hz), 1.28 (3H, s), 0.90 (3H, s)

The reference compounds 8-2 and 8-3 were obtained by using the compound1-1, and the reference compounds 7-1 and 7-2 in accordance with theproducing process of the reference compound 8-1.

(S)-7-[4-[2-(2,2-dimethyl-1,3-dioxolan-4-ylcarbonyloxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Reference Compound 8-2)

TABLE 16

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, dd, J = 8.8, 1.5 Hz), 6.93-6.84 (2H,m), 6.70 (1H, d, J = 7.8 Hz), 6.60-6.52 (2H, m), 6.38 (1H, td, J = 8.4,2.4 Hz), 6.04 (1H, d, J = 11.2 Hz), 5.44-5.35 (1H, m), 5.21 (1H, d, J =13.9 Hz), 4.84 (1H, d, J = 13.9 Hz), 4.65-4.57 (1H, m), 4.30-4.20 (1H,m), 4.17-4.03 (3H, m), 3.81 (3H, s), 3.68 (1H, s), 3.46 (3H, s), 2.01(3H, s), 1.52 (3H, d, J = 11.2 Hz), 1.43 (3H, d, J = 6.6 Hz), 1.40 (3H,s), 1.28 (3H, s), 0.90 (3H, s)

(S)-7-[4-[2-(N-t-butoxycarbonyl-2,2-dimethyl-1,3-dioxazolidin-4-ylcarbonyloxy)-propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Reference Compound 8-3)

TABLE 17

¹H-NMR (400 MHz, DMSO-d₆) δ 7.17 (1H, d, J = 8.1 Hz), 6.99 (1H, t, J =7.7 Hz), 6.78 (2H, s), 6.70-6.59 (2H, m), 6.48 (1H, td, J = 8.5, 2.1Hz), 6.12-6.02 (2H, m), 5.30-5.16 (2H, m), 4.82 (1H, d, J = 12.8 Hz),4.44-4.37 (1H, m), 4.22-4.06 (3H, m), 3.97-3.89 (1H, m), 3.78 (3H, s),3.33 (3H, s), 1.92 (3H, s), 1.56 (3H, s), 1.44-1.27 (15H, m), 1.07 (3H,s), 0.75 (3H, s)

Example 1(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 1-1)

In two pressure resistant reaction tubes with a volume of 200 mL werecharged8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound A, 7.5 g, 16.7 mmol), dehydrated ethanol (113 mL),potassium carbonate (11.5 g, 83.2 mmol) and (S)-(−)-propylene oxide (5.8mL, 82.9 mmol), respectively, and sealed, and stirred at 100° C.overnight. After allowing to cool, two reaction mixtures were combinedand concentrated under reduced pressure. Ethyl acetate (150 mL) wasadded to the residue, and the mixture was washed with water (150 mL×2times) and a saturated saline solution (150 mL). The organic layer wasdried over magnesium sulfate, and filtered. After the filtrate wasconcentrated under reduced pressure, 2-propanol (90 mL) was added to theresidue and the resulting mixture was stirred at room temperatureovernight. The precipitated solid was collected by filtration, andwashed with 2-propanol (7.5 mL). The solid was dried at 60° C. underreduced pressure to give the title compound (11.5 g) as a white solid(Yield: 68%).

TABLE 18

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (1H, d, J = 8.8 Hz), 6.93-6.84 (2H, m),6.71 (1H, d, J = 7.7 Hz), 6.62-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.2Hz), 6.04 (1H, dd, J = 11.4, 2.2 Hz), 5.22 (1H, d, J = 13.6 Hz), 4.84(1H, d, J = 13.6 Hz), 4.29-4.19 (1H, m), 4.05-3.97 (1H, m), 3.91-3.83(1H, m), 3.81 (3H, s), 3.69 (1H, s), 3.47 (3H, s), 2.31 (1H, d, J = 3.3Hz), 2.02 (3H, s), 1.32 (3H, d, J = 6.6 Hz), 1.28 (3H, s), 0.91 (3H, s)

8-(5-Fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxy-3,3,3-trifluoro-propyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 1-2)

A mixture of8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound A, 100 mg, 0.22 mmol),3-bromo-1,1,1-trifluoromethyl-2-propanol (46.0 μL, 0.44 mmol), cesiumcarbonate (145 mg, 0.44 mmol) and N,N-dimethylformamide (1.5 mL) wasstirred at 50° C. overnight. After allowing to cool at room temperature,water (50 mL) was added to the mixture and the resulting mixture wasextracted with ethyl acetate (50 mL). The organic layer was washed witha saturated saline solution (50 mL×2), dried over anhydrous magnesiumsulfate, and filtered. The filtrate was concentrated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (114mg) as a white solid (Yield: 91%).

TABLE 19

¹H-NMR (400 MHz, CDCl₃) δ 7.29-7.21 (1H, m), 6.94-6.84 (2H, m), 6.71(1H, d, J = 8.0 Hz), 6.63-6.58 (2H, m), 6.39 (1H, td, J = 8.3, 2.4 Hz),6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.20 (1H, d, J = 13.7 Hz), 4.82 (1H, d,J = 13.7 Hz), 4.45-4.36 (1H, m), 4.32 (1H, dd, J = 9.9, 3.3 Hz), 4.23(1H, dd, J = 9.9, 6.2 Hz), 3.82 (3H, s), 3.70 (1H, s), 3.46 (3H, s),2.84 (1H, d, J = 6.6 Hz), 2.02 (3H, s), 1.28 (3H, s), 0.93 (3H, s)

The compounds 1-3 to 1-6 were obtained by using the compound A and acommercially available compound in accordance with the productionprocess of the compound 1-1 or 1-2.

(R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 1-3)

TABLE 20

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 9.0 Hz), 6.94-6.84 (2H, m),6.70 (1H, d, J = 7.8 Hz), 6.63-6.55 (2H, m), 6.38 (1H, td, J = 8.4, 2.4Hz), 6.05 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84(1H, d, J = 13.7 Hz), 4.30-4.17 (1H, m), 4.04-3.98 (1H, m), 3.91-3.83(1H, m), 3.81 (3H, s), 3.77-3.64 (1H, m), 3.46 (3H, s), 2.31 (1H, d, J =3.4 Hz), 2.01 (3H, s), 1.32 (3H, d, J = 6.3 Hz), 1.28 (3H, s), 0.91 (3H,s)

(R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 1-4)

TABLE 21

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 9.0 Hz), 6.93-6.85 (2H, m),6.70 (1H, d, J = 8.0 Hz), 6.62-6.57 (2H, m), 6.38 (1H, td, J = 8.3, 2.5Hz), 6.04 (1H, dd, J = 11.3, 2.5 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.85(1H, d, J = 13.7 Hz), 4.05 (1H, dd, J = 8.5, 2.7 Hz), 4.01-3.87 (2H, m),3.81 (3H, s), 3.68 (1H, s), 3.47 (3H, s), 2.25 (1H, d, J = 2.7 Hz), 2.01(3H, s), 1.72-1.60 (2H, m), 1.28 (3H, s), 1.06 (3H, t, J = 7.4 Hz), 0.91(3H, s)

(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 1-5)

[TABLE 22]

¹H-NMR (400 MHz, CDCl₃) δ 7. 22 (1H, d, J = 8.8 Hz), 6. 93-6.84 (2H, m),6.70 (1H, d, J = 8.0 Hz), 6.62-6.56 (2H, m), 6.38 (1H, td, J = 8.4, 2.6Hz), 6.04 (1H, dd, J = 11.5, 2.6 Hz), 5.21 (1H, d, J = 13.6 Hz), 4.84(1H, d, J = 13.6 Hz), 4.05 (1H, dd, J = 9.0, 2.7 Hz), 4.02-3.87 (2H, m),3.81 (3H, s), 3.68 (1H, s), 3.47 (3H, s), 2.25 (1H, d, J = 2. 7 Hz),2.01 (3H, s), 1.71-1.60 (2H, m), 1.28 (3H, s), 1.06 (3H, t, J = 7.4 Hz),0.91 (3H, s)

(R)-7-[4-(2-ethoxycarbonyl-2-hydroxyethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 1-6)

[TABLE 23]

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 8.8 Hz), 6.93-6.83 (2H, m),6.70 (1H, d, J = 8.0 Hz), 6.62-6.55 (2H, m), 6.38 (1H, td, J = 8.3, 2.4Hz), 6.03 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.9 Hz), 4.83(1H, d, J = 13.9 Hz), 4.58-4.48 (1H, m), 4.38-4.26 (4H, m), 3.80 (3H,s), 3.69 (s, 1H), 3.46 (3H, s), 3.20 (1H, d, J = 6.6 Hz), 2.01 (3H, s),1.28 (3H, s), 1.21 (3H, t, J = 7.0 Hz), 0.90 (3H, s)

Example 2(S)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 2-1)

Palladium on carbon (50 mg) was added to a methanol (6 mL) solution of(S)-7-[4-(4-benzyloxy-2-hydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the reference compound 3-1, 254 mg, 0.405 mmol), and the mixture wasstirred under hydrogen atmosphere at room temperature overnight. Themixture was filtered, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (213mg) as white amorphous (Yield: 98%).

[TABLE 24]

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (1H, d, J = 8.8 Hz), 6.93-6.84 (2H, m),6.70 (1H, d, J = 7.8 Hz), 6.63-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.4Hz), 6.04 (1H, dd, J = 11.2, 2. 4 Hz), 5.21 (1H, d, J = 13. 7 Hz), 4.84(1H, d, J = 13.7 Hz), 4.37-4.25 (1H, m), 4.08-3.90 (4H, m), 3.81 (3H,s), 3.69 (1H, s), 3.46 (3H, s), 2.88 (1H, s), 2.23 (1H, t, J = 5.2 Hz),2.01 (3H, s), 1.93-1.81 (2H, m), 1.28 (3H, s), 0.91 (3H, s)

(R)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 2-2)

A mixture of8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound A, 451 mg, 1.0 mmol), (R)-4-benzyloxy-1,2-epoxybutane (thereference compound 2-2, 267 mg, 1.5 mmol), cesium carbonate (828 mg, 2.5mmol) and N,N-dimethylformamide (4.5 mL) was stirred at 70° C.overnight. After allowing to cool at room temperature, water (100 mL)was added to the mixture and the resulting mixture was extracted withethyl acetate (100 mL). The organic layer was washed with an aqueoussaturated ammonium chloride solution (100 mL) and a saturated salinesolution (100 mL), dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated under reduced pressure and the obtainedresidue was purified by silica gel column chromatography (hexane/ethylacetate). The obtained intermediate((R)-7-[4-(4-benzyloxy-2-hydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one)was dissolved in methanol (5.0 mL), palladium on carbon (30 mg) wasadded to the solution and the resulting mixture was stirred underhydrogen atmosphere at room temperature overnight. The mixture wasfiltered with methanol (30 mL) on celite. The filtrate was concentratedunder reduced pressure and the obtained residue was purified by silicagel column chromatography (chloroform/methanol) to give the titlecompound (341 mg) as white amorphous (Yield: 63%).

[TABLE 25]

¹H-NMR (400 MHz, CDCl₃) δ 7. 23 (1H, d, J = 8.8 Hz), 6. 93-6. 84 (2H,m), 6.70 (1H, d, J = 8.1 Hz), 6.62-6.56 (2H, m), 6.38 (1H, td, J = 8.3,2.4 Hz), 6.04 (1H, dd, J = 11.4, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz),4.84 (1H, d, J = 13.7 Hz), 4.36-4.26 (1H, m), 4.08-3.90 (4H, m), 3.81(3H, s), 3.69 (1H, s), 3.47 (3H, s), 2.89 (1H, s), 2.24 (1H, t, J = 4. 9Hz), 2.01 (3H, s), 1.94-1.84 (2H, m), 1.28 (3H, s), 0.91 (3H, s)

The compound 2-3 was obtained by using the reference compound 8-1 inaccordance with the producing process of the compound 2-1.

(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxyacetoxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 2-3)

[TABLE 26]

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 8.8 Hz), 6.93-6.84 (2H, m),6.71 (1H, d, J = 7.7 Hz), 6.59-6.54 (2H, m), 6.39 (1H, td, J = 8.3, 2.4Hz), 6.04 (1H, dd, J = 11.4, 2.4 Hz), 5.48-5.38 (1H, m), 5.21 (1H, d, J= 13.6 Hz), 4.83 (1H, d, J = 13.6 Hz), 4.20 (2H, s), 4.14-4.04 (2H, m),3.81 (3H, s), 3.46 (3H, s), 2.38 (1H, s), 2.01 (3H, s), 1.44 (3H, d, J =6.6 Hz), 1.29 (3H, s), 0.91 (3H, s)

Example 38-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxyethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 3-1)

1N hydrochloric acid (2.0 mL) was added to a tetrahydrofuran-methanolmixed solution (1:1, 4.0 mL) of8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-tetrahydropyran-2-yloxyethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the reference compound 4-1, 130 mg, 0.22 mmol), and the resultingmixture was stirred at room temperature overnight. The mixture wasdiluted with ethyl acetate (20 mL), and the organic layer was washedwith a saturated aqueous sodium hydrogen carbonate solution (20 mL) anda saturated saline solution (20 mL). The organic layer was dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedunder reduced pressure and the obtained residue was purified by silicagel column chromato-graphy (hexane/ethyl acetate) to give the titlecompound (72 mg) as a colorless oily product (Yield: 65%).

[TABLE 27]

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (1H, d, J = 8.8 Hz), 6.93-6.84 (2H, m),6.71 (1H, d, J = 8.0 Hz), 6.64-6.57 (2H, m), 6.38 (1H, td, J = 8.4, 2.4Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.22 (1H, d, J = 13.7 Hz), 4.85(1H, d, J = 13.7 Hz), 4.21-4.12 (2H, m), 4.05-3.97 (2H, m), 3.81 (3H,s), 3.69 (1H, s), 3.47 (3H, s), 2.02 (3H, s), 1.28 (3H, s), 0.91 (3H, s)

Example 47-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 4-1)

Under ice-cooling, trifluoroacetic acid (4.0 mL) was added to amethylene chloride (20 mL) solution of7-[4-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the reference compound 5-1, 685 mg, 1.2 mmol) and the resulting mixturewas stirred at room temperature for 3 hours. Water (1.0 mL) was added tothe mixture, and the resulting mixture was further stirred at roomtemperature for 1 hour. The mixture was concentrated under reducedpressure, and the obtained residue was diluted with ethyl acetate (150mL). The organic layer was washed with a saturated aqueous sodiumhydrogen carbonate solution (100 mL) and a saturated saline solution(100 mL), dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure and the obtainedresidue was purified by silica gel column chromatography (hexane/ethylacetate) to give the title compound (556 mg) as white amorphous (Yield:88%).

[TABLE 28]

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (1H, d, J = 8.5 Hz), 6.93-6.83 (2H, m),6.71 (1H, d, J = 8.0 Hz), 6.63-6.57 (2H, m), 6.39 (1H, td, J = 8.3, 2.4Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.20 (1H, d, J = 13.4 Hz), 4.83(1H, d, J = 13. 4 Hz), 4.20-4.08 (3H, m), 3.93-3.75 (2H, m), 3.81 (3H,s), 3.69 (1H, s), 3.46 (3H, s), 2.58 (1H, d, J = 4.1 Hz), 2.02 (3H, s),1.98 (1H, t, J = 6.3 Hz), 1.28 (3H, s), 0.92 (3H, s)

The compounds 4-2 and 4-3 were obtained by using the reference compounds5-1 and 5-2 in accordance with the producing process of the compound4-1.

(S)-7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 4-2)

[TABLE 29]

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (1H, d, J = 8.5 Hz), 6.94-6.84 (2H, m),6.71 (1H, d, J = 8.0 Hz), 6.64-6.56 (2H, m), 6.39 (1H, td, J = 8.2, 2.4Hz), 6.04 (1H, dd, J = 11.0, 2.4Hz), 5.21 (1H, d, J = 13.7 Hz), 4.83(1H, d, J = 13.7 Hz), 4.20-4.06 (3H, m), 3.93-3.74 (2H, m), 3.81 (3H,s), 3.69 (1H, s), 3.46 (3H, s), 2.56 (1H, d, J = 4.4 Hz), 2.02 (3H, s),1.96 (1H, t, J = 5.9 Hz), 1.28 (3H, s), 0.92 (3H, s)

(R)-7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 4-3)

[TABLE 30]

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (1H, d, J = 8.1 Hz), 6.94-6.86 (211, m),6.73-6.55 (3H, m), 6.39 (1H, td, J = 8.4, 2.2 Hz), 6.03 (1H, dd, J =11.0, 2.2 Hz), 5.20 (1H, d, J = 13.4 Hz), 4.83 (1H, d, J = 13.4 Hz),4.20-4.08 (3H, m), 3.92-3.76 (2H, m), 3.81 (3H, s), 3.47 (3H, s), 2.01(3H, s), 1.28 (3H, s), 0.96 (3H, s)

Example 5(R)-7-[4-(3-cyano-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 5-1)

A mixture of(R)-7-[4-(2,3-epoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the reference compound 5-4, 235 mg, 0.46 mmol), potassium cyanide (66mg, 1.0 mmol), water (0.90 mL) and N,N-dimethylformamide (5.0 mL) wasstirred at room temperature overnight. To the mixture was added asaturated saline solution (30 mL), and the resulting mixture wasextracted with ethyl acetate (30 mL×3). The organic layer was washedwith a saturated saline solution (40 mL), dried over anhydrous magnesiumsulfate, and filtered. The filtrate was concentrated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (208mg) as white amorphous (Yield: 87%).

[TABLE 31]

¹H-NMR (400 MHz, CDCl₃) δ 7.24 (1H, d, J = 9.0 Hz), 6.90 (1H, t, J = 7.7Hz), 6.87 (1H, d, J = 8.0 Hz), 6.71 (1H, d, J = 8.0 Hz), 6.62-6.56 (2H,m), 6.39 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz),5.20 (1H, d, J = 13.4 Hz), 4.82 (1H, d, J = 13.4 Hz), 4.43-4.34 (1H, m),4.19-4.08 (2H, m), 3.81 (3H, s), 3.70 (1H, s), 3.46 (3H, s), 2.87-2.71(2H, m), 2.64 (1H, d, J = 5.4 Hz), 2.02 (3H, s), 1.28 (3H, s), 0.93 (3H,s)

The compound 5-2 was obtained by using the reference compound 5-5 and acommercially available compound in accordance with the producing processof the compound 5-1.

(S)-7-[4-(3-cyano-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 5-2)

[TABLE 32]

¹H-NMR (400 MHz, CDCl₃) δ 7.24 (1H, d, J = 9.0 Hz), 6.90 (1H, t, J = 7.7Hz), 6.87 (1H, d, J = 8.0 Hz), 6.71 (1H, d, J = 8.0 Hz), 6.61-6.56 (2H,m), 6.39 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz),5.20 (1H, d, J = 13.4 Hz), 4.83 (1H, d, J = 13.4 Hz), 4.43-4.31 (1H, m),4.20-4.07 (2H, m), 3.81 (3H, s), 3.71 (1H, s), 3.46 (3H, s), 2.86-2.72(2H, m), 2.70 (1H, d, J = 5.4 Hz), 2.02 (3H, s), 1.28 (3H, s), 0.93 (3H,s)

Example 67-[4-(3-fluoro-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 6-1)

Under ice-cooling, N,N-diethylaminosulfur trifluoride (76 μL, 0.58 mmol)was added to a methylene chloride (4.0 mL) solution of7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound 4-1, 200 mg, 0.38 mmol) and the resulting mixture wasstirred for 3 hours. The mixture was filtered using silica gel and thefiltrate was washed with ethyl acetate (20 mL×3). The filtrate wasconcentrated under reduced pressure and the obtained residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (22 mg) as white amorphous (Yield: 11%).

[TABLE 33]

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (1H, d, J = 8. 5 Hz), 6.94-6.84 (2H, m),6.71 (1H, d, J = 7.8 Hz), 6.63-6.56 (2H, m), 6.39 (1H, td, J = 8.3, 2.4Hz), 6.04 (1H, dd, J = 1.13, 2.4 Hz), 5.20 (1H, d, J = 13.7 Hz), 4.83(1H, d, J = 13.7 Hz), 4.74-4.63 (1H, m), 4.62-4.51 (1H, m), 4.36-4.23(1H, m), 4.19-4.09 (2H, m), 3.81 (3H, s), 3.69 (1H, s), 3.46 (3H, s),2.41 (1H, d, J = 5. 6 Hz), 2.02 (3H, s), 1.28 (3H, s), 0.92 (3H, s)

Example 77-[4-(3-ethoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 7-1)

Under argon gas atmosphere, an n-butyllithium 1.6M hexane solution (4.2mL, 6.7 mmol) was added to a mixed solution of anhydrous tetrahydrofuran(8.0 mL) and N,N-diisopropylamine (0.95 mL, 6.8 mmol) under ice-coolingand the resulting mixture was stirred for 30 minutes. The mixture wascooled to −78° C., and ethyl acetate (0.66 mL, 6.8 mmol) was addedthereto and the resulting mixture was stirred for 1 hour. To the mixturewas added dropwise an anhydrous tetrahydrofuran (8 mL) solution of8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(methoxycarbonylmethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the reference compound 6-1, 2.4 g, 4.6 mmol) over 5 minutes. Themixture was stirred accompanying with raising of the temperature for 2.5hours, and 1N hydrochloric acid (15 mL) was added at −16° C. Water (50mL) was added to the mixture and the resulting mixture was extractedwith ethyl acetate (100 mL). The organic layer was washed with anaqueous saturated ammonium chloride solution (50 mL) and a saturatedsaline solution (50 mL). The organic layer was dried over anhydrousmagnesium sulfate, and filtered. The filtrate was concentrated underreduced pressure, and the obtained intermediate(7-[4-(3-ethoxycarbonyl-2-oxopropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one)was dissolved in tetrahydrofuran (25 mL). Under ice-cooling, to thesolution was added sodium borohydride (0.35 g, 9.3 mmol) and the mixturewas stirred for 15 minutes. To the mixture were added water (50 mL) and1N hydrochloric acid (15 mL), and the resulting mixture was extractedwith ethyl acetate (100 mL). The organic layer was washed with anaqueous saturated ammonium chloride solution (50 mL) and a saturatedsaline solution (50 mL). The organic layer was concentrated underreduced pressure and the obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate) to give the title compound(1.4 g) as white amorphous (Yield: 54%).

[TABLE 34]

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (1H, d, J = 8.8 Hz), 6.93-6.84 (2H, m),6.70 (1H, d, J = 8.0 Hz), 6.62-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.4Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84(1H, d, J = 13.7 Hz), 4.52-4.40 (1H, m), 4.22 (2H, q, J = 7.2 Hz), 4.07(2H, d, J = 5.4 Hz), 3.81 (3H, s), 3.69 (1H, s), 3.46 (3H, s), 3.16 (1H,d, J = 4.4 Hz), 2.74-2.68 (2H, m), 2.01 (3H, s), 1.33-1.23 (6H, m), 0.91(3H, s)

The compound 7-2 was obtained by using the reference compound 6-1 and acommercially available compound in accordance with the producing processof the compound 7-1.

7-[4-(3-t-butoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 7-2)

[TABLE 35]

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 8.5 Hz), 6.93-6.84 (2H, m),0.70 (1H, d, J = 7.8 Hz), 6.62-6.56 (2H, m), 6.38 (1H, td, J = 8.4, 2.4Hz), 6.04 (1H, dd, J = 11.2, 2. 4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84(1H, d, J = 13.7 Hz), 4.47-4.36 (1H, m), 4.09-4.00 (2H, m), 3.80 (3H,s), 3.68 (1H, s), 3.46 (3H, s), 3.26 (1H, d, J = 4.4 Hz), 2.70-2.56 (2H,m), 2.01 (3H, s), 1.49 (9H, s), 1.28 (3H, s), 0.91 (3H, s)

Example 87-[4-(3,3-dimethyl-2-hydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 8-1)

Under ice-cooling, sodium borohydride (9.0 mg, 0.24 mmol) was added to amethanol (1.0 mL) solution of7-[4-(3,3-dimethyl-2-oxobutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the reference compound 5-6, 55 mg, 0.10 mmol), and the resultingmixture was stirred for 1 hour. To the mixture was added 1N hydrochloricacid (20 mL), and the resulting mixture was extracted with ethyl acetate(15 mL×2). The organic layers were combined and washed with a saturatedaqueous sodium hydrogen carbonate solution (20 mL) and a saturatedsaline solution (20 mL), dried over anhydrous magnesium sulfate, andfiltered. The filtrate was concentrated under reduced pressure to givethe title compound (51 mg) as pink amorphous (Yield: 92%).

[TABLE 36]

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (1H, d, J = 8.5 Hz), 6.93-6.84 (2H, m),6.70 (1H, d, J = 8.0 Hz), 6.63-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.4Hz), 6.05 (1H, dd, J = 11.2, 2.4 Hz), 5.22 (1H, d, J = 13.7 Hz), 4.85(1H, d, J = 13.7 Hz), 4.22-4.14 (1H, m), 3.93 (1H, t, J = 9.0 Hz), 3.81(3H, s), 3.77-3.64 (2H, m), 3.47 (3H, s), 2.37 (1H, d, J = 2.9 Hz), 2.02(3H, s), 1.28 (3H, s), 1.04 (9H, s), 0.91 (3H, s)

Example 9

7-[4-(3-Carboxy-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound 9-1) A mixture of7-[4-(3-ethoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound 7-1, 1.9 g, 3.3 mmol), 4N aqueous sodium hydroxidesolution (10 mL) and methanol (15 mL) was stirred at 50° C. overnight.After allowing to cool at room temperature, 1N hydrochloric acid (45 mL)was added to the mixture. The precipitated solid was collected byfiltration, and washed with water (50 mL). The obtained solid was driedunder reduced pressure at 40° C. for 4 hours to give the title compound(1.6 g) as reddish brown solid (Yield: 88%).

TABLE 37

¹H-NMR (400 MHz, DMSO-d₆) δ 12.19 (1H, s), 7.16 (1H, d, J = 8.4 Hz),6.98 (1H, t, J = 7.7 Hz), 6.81-6.73 (2H, m), 6.68 (1H, d, J = 2.3 Hz),6.64 (1H, dd, J = 8.3, 2.3 Hz), 6.48 (1H, td, J = 8.3, 2.3 Hz),6.12-6.00 (2H, m), 5.31-5.13 (2H, m), 4.83 (1H, d, J = 13.9 Hz),4.27-4.16 (1H, m), 3.97 (2H, d, J = 5.1 Hz), 3.79 (3H, s), 3.32 (3H, s),2.62-2.34 (2H, m), 1.92 (3H, s), 1.07 (3H, s), 0.74 (3H, s)

Example 108-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-pyrrolidylcarbonyl)-2-hydroxypropyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 10-1)

A mixture of7-[4-(3-carboxy-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound 9-1, 110 mg, 0.20 mmol), 1-hydroxybenzotriazole (48 mg,0.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(59 mg, 0.31 mmol), pyrrolidine (33 μL, 0.40 mmol), N-methylmorpholine(88 μL, 0.80 mmol) and N,N-dimethylformamide (2.0 mL) was stirred atroom temperature overnight. A saturated saline solution (10 mL) wasadded to the mixture, and the resulting mixture was extracted with ethylacetate (10 mL×2). The organic layer was washed with a saturated salinesolution (20 mL), dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated under reduced pressure and the obtainedresidue was purified by silica gel column chromatography(chloroform/methanol) to give the title compound (24 mg) as pale brownamorphous (Yield: 20%).

TABLE 38

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 8.8 Hz), 6.94-6.83 (2H, m),6.70 (1H, d, J = 8.1 Hz), 6.64-6.57 (2H, m), 6.38 (1H, td, J = 8.3, 2.4Hz 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H,d, J = 13.7 Hz), 4.66 (1H, d, J = 3.7 Hz), 4.52-4.40 (1H, m), 4.17-4.01(2H, m), 3.80 (3H, s), 3.68 (1H, s), 3.55-3.41 (7H, m), 2.75-2.54 (2H,m), 2.06-1.81 (7H, m), 1.28 (3H, s), 0.91 (3H, s)

The compounds 10-2 and 10-3 were obtained by using the compound 9-1 anda commercially available compound in accordance with the producingprocess of the compound 10-1.

8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-morpholino)carbonyl-2-hydroxypropyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 10-2)

TABLE 39

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 8.4 Hz), 6.94-6.84 (2H, m),6.70 (1H, d, J = 8.1 Hz), 6.64-6.56 (2H, m), 6.39 (1H, td, J = 8.2, 2.4Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84(1H, d, J = 13.7 Hz), 4.55-4.42 (1H, m), 4.20 (1H, d, J = 4.0 Hz),4.18-4.01 (2H, m), 3.80 (3H, s), 3.75-3.59 (7H, m), 3.55-3.48 (2H, m),3.46 (3H, s), 2.79-2.59 (2H, m), 2.02 (3H, s), 1.28 (3H, s), 0.91 (3H,s)

8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-piperidino)carbonyl-2-hydroxy-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 10-3)

TABLE 40

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 8.4 Hz), 6.94-6.83 (2H, m),6.70 (1H, d, J = 8.1 Hz), 6.65-6.57 (2H, m), 6.38 (1H, td, J = 8.2, 2.46.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.6 Hz), 4.84 (1H, d,J = 13.6 Hz), 4.54 (1H, d, J = 3.7 Hz), 4.51-4.39 (1H, m), 4.18-4.00(2H, m), 3.80 (3H, s), 3.72-3.50 (3H, m), 3.49-3.38 (5H, m), 2.80-2.56(2H, m), 2.01 (3H, s), 1.73-1.47 (6H, m), 1.28 (3H, s), 0.91 (3H, s)

Example 11(S)-7-[4-[2-(N,N-dimethylaminoacetoxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 11-1)

To N,N-dimethylformamide-methylene chloride mixed solution (1:1, 12 mL)were 5 added(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound 1-1, 509 mg, 1.00 mmol), N,N-dimethylglycine (207 mg, 2.01mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (388mg, 2.02 mmol) and 4-dimethylaminopyridine (10.6 mg, 0.087 mmol), andthe mixture was stirred at 50° C. for 6 hours. After allowing to cool,the mixture was diluted with ethyl acetate (100 mL), and washed with asaturated aqueous sodium hydrogen carbonate solution (50 mL), an aqueoussaturated ammonium chloride solution (50 mL) and a saturated salinesolution (50 mL). The organic layer was concentrated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (205mg) as white amorphous (Yield: 35%).

TABLE 41

¹H-NMR (400 MHz, DMSO-d₆) δ 7.17 (1H, d, J = 8.3 Hz), 6.99 (1H, t, J =7.7 Hz), 6.78 (2H, s), 6.71-6.62 (2H, m), 6.48 (1H, td, J = 8.4, 2.4Hz), 6.08 (2H, m), 5.31-5.16 (2H, m), 4.83 (1H, d, J = 13.7 Hz),4.15-4.10 (2H, m), 3.79 (3H, s), 3.32 (3H, s), 3.16 (2H, s), 2.23 (6H,s), 1.92 (3H, s), 1.31 (3H, d, J = 6.3 Hz), 1.07 (3H, s), 0.75 (3H, s)

8-(5-Fluoro-2-methylphenoxymethyl)-7-[4-[(2S)-[(2S)-pyrrolidylcarbonyloxy]-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-onehydrochloride (the Compound 11-2)

A mixture of(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxy-propyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound 1-1, 306 mg, 0.60 mmol), N-t-butoxycarbonyl-L-proline (258mg, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (234 mg, 1.2 mmol), 4-dimethylaminopyridine (9.9 mg, 0.081mmol) and methylene chloride (6.0 mL) was stirred at room temperatureovernight. The mixture was concentrated under reduced pressure, and theobtained residue was diluted by ethyl acetate (50 mL) and washed withwater (50 mL). The organic layer was concentrated under reduced pressureand the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate). A 4N hydrochloricacid-1,4-dioxane solution (8.0 mL) was added to the obtainedintermediate(7-[4-[(2S)—[(S)—N-(t-butoxycarbonyl)pyrrolidin-2-ylcarbonyloxy]propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one),and the resulting mixture was stirred at room temperature overnight. Themixture was concentrated under reduced pressure, and diethyl ether (10mL) and ethyl acetate (10 mL) were added to the obtained residue. Theprecipitated solid was collected by filtration, and washed with ethylacetate (10 mL). The obtained solid was dried under reduced pressure at40° C. for 3.5 hours to give the title compound (284 mg) as a whitesolid (Yield: 74%).

TABLE 42

¹H-NMR (400 MHz, DMSO-d₆) δ 9.92 (1H, s), 8.96 (1H, s), 7.18 (1H, d, J =8.4 Hz), 6.99 (1H, t, J = 7.5 Hz), 6.78 (2H, s), 6.70-6.63 (2H, m), 6.49(1H, td, J = 8.4, 2.4 Hz), 6.19-6.00 (2H, m), 5.40-5.29 (1H, m), 5.23(1H, d, J = 13.6 Hz), 4.82 (1H, d, J = 13.6 Hz), 4.48-4.10 (5H, m), 3.79(3H, s), 3.32 (3H, s), 3.29-3.12 (2H, m), 2.01-1.82 (5H, m), 1.38 (3H,d, J = 6.6 Hz), 1.07 (3H, s), 0.74 (3H, s)

The compounds 11-3 to 11-5 were obtained by using the compound 1-1 and acommercially available compound in accordance with the producing processof the compound 11-1 or 11-2.

(R)-7-[4-[2-(N,N-dimethylaminoacetoxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 11-3)

TABLE 43

¹H-NMR (400 MHz, DMSO-d₆) δ 7.17 (1H, d, J = 8.3 Hz), 6.99 (1H, t, J =7.7 Hz), 6.77 (2H, s), 6.71-6.61 (2H, m), 6.48 (1H, td, J = 8.4, 2.4Hz), 6.12-6.03 (2H, m), 5.28-5.17 (2H, m), 4.83 (1H, d, J = 14.2 Hz),4.18-4.08 (2H, m), 3.79 (3H, s), 3.32 (3H, s), 3.15 (2H, s), 2.23 (6H,s), 1.92 (3H, s), 1.31 (3H, d, J = 6.3 Hz), 1.07 (3H, s), 0.75 (3H, s)

(S)-7-[4-(2-aminoacetoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-onehydrochloride (the Compound 11-4)

TABLE 44

¹H-NMR (400 MHz, DMSO-d₆) δ 8.33 (3H, s), 7.18 (1H, d, J = 8.3 Hz), 6.99(1H, t, J = 7.7 Hz), 6.78 (2H, s), 6.71-6.63 (2H, m), 6.49 (1H, td, J =8.4, 2.4 Hz), 6.17-6.01 (2H, m), 5.36-5.27 (1H, m), 5.22 (1H, d, J =14.3 Hz), 4.81 (1H, d, J = 14.3 Hz), 4.22-4.11 (2H, 1H), 3.91-3.82 (2H,m), 3.80 (3H, s), 3.33 (3H, s), 1.92 (3H, s), 1.37 (3H, d, J = 6.3 Hz),1.07 (3H, s), 0.75 (3H, s)

7-[4-[(2S)-[(2S)-amino-3-methylbutanoyloxy]propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-onehydrochloride (the Compound 11-5)

TABLE 45

¹H-NMR (400 MHz, DMSO-d₆) δ 8.46 (3H, s), 7.18 (1H, d, J = 9.0 Hz), 6.99(1H, t, J = 7.7 Hz), 6.78 (2H, s), 6.68-6.59 (2H, m), 6.49 (1H, td, J =8.5, 2.3 Hz), 6.18-6.01 (2H, m), 5.42-5.31 (1H, m), 5.22 (1H, d, J =14.1 Hz), 4.81 (1H, d, J = 14.1 Hz), 4.29-4.20 (1H, m), 4.19-4.09 (1H,m), 3.98-3.89 (1H, m), 3.78 (3H, s), 3.32 (3H, s), 2.23-2.10 (1H, m),1.92 (3H, s), 1.36 (3H, d, J = 6.6 Hz), 1.07 (3H, s), 1.02-0.92 (6H, m),0.75 (3H, s)

Example 12(S)-7-[4-[2-(3-carboxypropanoyloxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 12-1)

A mixture of(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxy-propyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound 1-1, 52 mg, 0.10 mmol), succinic anhydride (16 mg, 0.16mmol), 4-dimethylaminopyridine (catalytic amount) and pyridine (0.5 mL)was stirred at room temperature overnight. Succinic anhydride (65 mg,0.65 mmol) was additionally added and the mixture was further stirredovernight. The mixture was diluted with ethyl acetate (10 mL), and theorganic layer was washed with 1N hydrochloric acid (15 mL×2) and asaturated saline solution (5 mL). The organic layer was dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give the title compound (58 mg) as whiteamorphous (quantitative).

TABLE 46

¹H-NMR (400 MHz, CDCl₃) δ 7.22 (1H, d, J = 8.4 Hz), 6.92-6.84 (2H, m),6.70 (1H, d, J = 8.1 Hz), 6.61-6.55 (2H, m), 6.38 (1H, td, J = 8.3, 2.4Hz), 6.04 (1H, dd, J =11.2, 2.4 Hz), 5.37-5.29 (1H, m), 5.21 (1H, d, J =13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.16-3.99 (2H, m), 3.81 (3H, s),3.46 (3H, s), 2.76-2.61 (4H, m), 2.01 (3H, s), 1.40 (3H, d, J = 6.6 Hz),1.28 (3H, s), 0.90 (3H, s)

Example 13(S)-7-[4-[2-(2,3-dihydroxypropanoyl)oxypropyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 13-1)

A mixture of(S)-7-[4-[2-(2,2-dimethyl-1,3-dioxolan-4-ylcarbonyloxy)propyl]-oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the reference compound 8-2, 70 mg, 0.11 mmol), 2N hydrochloric acid(1.0 mL) and methanol (4.0 mL) was stirred at 50° C. for 1 hour. Afterallowing to cool at room temperature, the mixture was concentrated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate) to give the title compound(35 mg) as a white solid (Yield: 54%)

TABLE 47

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (1H, d, J = 8.8 Hz), 6.93-6.83 (2H, m),6.70 (1H, d, J = 8.1 Hz), 6.61-6.53 (2H, m), 6.38 (1H, td, J = 8.3, 2.4Hz), 6.08-6.00 (1H, m), 5.50-5.38 (1H, m), 5.21 (1H, d, J = 13.9 Hz),4.83 (1H, d, J = 13.9 Hz), 4.34-4.27 (1H, m), 4.15-4.06 (2H, m),3.94-3.84 (2H, m), 3.81 (3H, d, J = 2.7 Hz), 3.69 (1H, s), 3.46 (3H, s),3.10 (1H, dd, J = 11.5, 4.9 Hz), 2.01 (3H, s), 1.45 (3H, dd, J = 6.5,1.6 Hz), 1.28 (3H, s), 1.21 (1H, t, J = 7.1 Hz), 0.91 (3H, s)

The compound 13-2 was obtained by using the reference compound 8-3 inaccordance with the producing process of the compound 13-1.

7-[4-[(2S)-[(2S)-amino-3-hydroxypropanoyloxy]propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 13-2)

TABLE 48

¹H-NMR (400 MHz, DMSO-d₆) δ 7.17 (1H, d, J = 8.1 Hz), 6.98 (1H, t, J =7.7 Hz), 6.77 (2H, s), 6.71-6.62 (2H, m), 6.48 (1H, td, J = 8.4, 2.6Hz), 6.12-6.04 (2H, m), 5.27-5.12 (2H, m), 4.88-4.74 (2H, m), 4.11 (2H,d, J = 5.5 Hz), 3.79 (3H, s), 3.56-3.49 (2H, m), 3.30 (3H, s), 1.92 (3H,s), 1.75 (2H, s), 1.32 (3H, d, J = 6.2 Hz), 1.06 (3H, s), 0.74 (3H, s)

Example 14(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-phosphonohydroxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 14-1)

Under ice-cooling, a methylene chloride (3.0 mL) solution ofm-chloro-perbenzoic acid (41 mg, 0.24 mmol) was added dropwise to anN,N-dimethylformamide (3.0 mL) solution of(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)-oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the compound 1-1, 100 mg, 0.20 mmol), 1H-tetrazole (62 mg, 0.89 mmol)and di-t-butoxy(diisopropylamino)phosphine (0.19 mL, 0.60 mmol), and themixture was stirred for 1 hour. To the mixture were added a saturatedaqueous sodium hydrogen carbonate solution (5 mL) and water (50 mL), andthe resulting mixture was extracted with ethyl acetate (50 mL×2). Theorganic layers were combined, washed with a saturated saline solution(50 mL), dried over anhydrous sodium sulfate, and filtered. The filtratewas concentrated under reduced pressure and the obtained residue waspurified by silica gel column chromatography (hexane/ethyl acetate). Theobtained intermediate((S)-7-[4-[2-(di-t-butylphosphonohydroxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one)was dissolved in anhydrous methylene chloride (1 mL). Under ice-cooling,trifluoroacetic acid (1 mL) was added to the solution, and the resultingmixture was stirred at room temperature for 30 minutes. The mixture wasconcentrated under reduced pressure, and hexane-diethyl ether (1:1, 2mL) was added to the obtained residue. The precipitated solid wascollected by filtration, and washed with hexane-diethyl ether (1:1, 5mL). The obtained solid was dried to give the title compound (49 mg) asa white solid (Yield: 42%).

TABLE 49

¹H-NMR (500 MHz, DMSO-d₆) δ 7.17 (1H, d, J = 8.2 Hz), 6.99 (1H, t, J =7.6 Hz), 6.77 (2H, dd, J = 10.2, 8.2 Hz), 6.70 (1H, s), 6.65 (1H, d, J =8.2 Hz), 6.48 (1H, td, J = 8.4, 2.4 Hz), 6.11-6.04 (2H, m), 5.22 (1H, d,J = 13.7 Hz), 4.83 (1H, d, J = 13.7 Hz), 4.61-4.51 (1H, m), 4.13-4.02(2H, m), 3.80 (3H, s), 3.33 (3H, s), 1.92 (3H, s), 1.36 (3H, d, J = 6.4Hz), 1.07 (3H, s), 0.74 (3H, s)

The compounds 14-2 and 14-3 were obtained by using the compounds 1-5,5-2 and a commercially available compound in accordance with theproducing process of the compound 14-1.

(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-phosphonohydroxybutyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 14-2)

TABLE 50

¹H-NMR (400 MHz, DMSO-d₆) δ 7.17 (1H, d, J = 8.3 Hz), 6.98 (1H, t, J =7.7 Hz), 6.77 (2H, dd, J = 9.2, 8.3 Hz), 6.71 (1H, s), 6.66 (1H, d, J =8.3 Hz), 6.48 (1H, td, J = 8.3, 2.4 Hz), 6.12-6.03 (2H, m), 5.23 (1H, d,J = 14.2 Hz), 4.84 (1H, d, J = 14.2 Hz), 4.42-4.30 (1H, m), 4.19-4.07(2H, m), 3.80 (3H, s), 3.33 (3H, s), 1.92 (3H, s), 1.84-1.65 (2H, m),1.07 (3H, s), 0.96 (3H, t, J = 7.4 Hz), 0.74 (3H, s)

(S)-7-[4-(3-cyano-2-phosphonohydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one(the Compound 14-3)

TABLE 51

¹H-NMR (400 MHz, DMSO-d₆) δ 7.22-7.12 (1H, m), 7.02-6.93 (1H, m),6.81-6.65 (4H, m), 6.48 (1H, td, J = 8.2, 2.1 Hz), 6.13-6.03 (2H, m),5.22 (1H, d, J = 13.4 Hz), 4.91-4.59 (2H, m), 4.29-4.17 (2H, m), 3.80(3H, s), 3.33 (3H, s), 3.08-3.03 (2H, m), 1.92 (3H, s), 1.07 (3H, s),0.75 (3H, s)

[Pharmacological Test]

For carrying out Pharmacological Test, the control compound B, thecontrol compound C, the control compound D, the control compound E andthe control compound F were prepared in accordance with theabove-mentioned Patent Document 2 (JP 2008-74829A) for comparison withthe effect of the present compound, and used in the test.

The control compound B is8-(5-fluoro-2-methylphenoxymethyl)-7-(5-hydroxymethyl-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-onehaving the following structure:

The control compound C is8-(5-fluoro-2-methylphenoxymethyl)-7-(5-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-onehaving the following structure:

The control compound D is7-(4-butyryloxy-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-onehaving the following structure:

The control compound E is7-(2,4-dimethoxyphenyl)-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-onehaving the following structure:

The control compound F is8-(5-fluoro-2-methylphenoxymethyl)-7-(2-methoxy-4-methoxymethoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-onehaving the following structure:

[Pharmacological Test] 1. GR Binding Activity Evaluation Test

In order to evaluate a binding activity of the present compound to GR, aGR receptor competitor assay was carried out by a fluorescencepolarization method. In the assay, a GR competitive binding assay kit(manufactured by Invitrogen, cat No. P2816) was used for the assay, anda procedure was carried out according to the protocol attached to thekit. Hereinafter, the specific method will be described.

(Preparation of Reagents)

GR screening buffer: A buffer containing 10 mM of potassium phosphate(pH 7.4), 20 mM of sodium molybdate (Na₂MoO₄), 0.1 mM of ethylenediamine tetraacetic acid (EDTA), 5 mM of dithiothreitol (DTT), 0.1 mM ofstabilizing peptide and 2% of dimethylsulfoxide was prepared.

4×GS1 solution: Fluormone™ GS1, which is a fluorescent glucocorticoidligand, was diluted with GR screening buffer, whereby a 4 nM solutionwas prepared.

4×GR solution: Recombinant human GR was diluted with GR screeningbuffer, whereby a 16 nM solution was prepared.

(Preparation of Test Compound Solution and Dexamethasone (HereinafterAlso Referred to as “DEX”.) Solution)

After a test compound was dissolved in dimethylsulfoxide, the resultingsolution was diluted with GR screening buffer, whereby a 20 μM testcompound solution was prepared. In addition, DEX was similarlydissolved, whereby a DEX solution with a 200 μM concentration wasprepared, and the solution was diluted with GR screening buffer, wherebya 2 mM DEX solution was prepared. DEX was used as positive control.

(Test Method and Measurement Method)

1) The test compound solution was added in an amount of 10 μL into eachwell of a 384-well plate.2) 4×GS1 solution and 4×GR solution were added in an amount of 5 μL intoeach well, respectively.3) GR screening buffer was added in an amount of 10 μL/well into eachwell in place of the test compound solution, which was made a negativecontrol.4) A 2 mM of DEX was added in an amount of 10 μL/well into each well inplace of the test compound solution, which was made a positive control.5) The plate was incubated in a dark place at room temperature for 2hours, and fluorescence polarization of each well was measured.

(Calculation Equation of GR Binding Ratio)

A GR binding ratio (%) was calculated from the following equation.

GR binding ratio(%)=100×{1−(fluorescence polarization of test compoundsolution−average value of fluorescence polarization of positive controlsolution)/(average value of fluorescence polarization of negativecontrol solution−average value of fluorescence polarization of positivecontrol solution)}

(Test Results and Discussion)

The GR binding rates (%) when the compound 1-1, the compound 1-3, thecompound 1-4, the compound 1-6, the compound 2-1, the compound 2-2, thecompound 3-1, the compound 4-1, the compound 4-2, the compound 4-3, thecompound 5-1, the compound 5-2, the compound 7-1, the compound 7-2, thecompound 9-1, the compound 10-1, the compound 10-2, the compound 10-3,the compound 11-1, the compound 11-5, the compound 14-1, the controlcompound B, the control compound C, the control compound D, the controlcompound E and the control compound F were used as the test compound areshown in Table I.

As a result of the GR binding activity evaluation test, the presentcompounds showed an excellent GR binding activity.

TABLE I Test compound GR binding rate (%) Compound 1-1 >99 Compound 1-395 Compound 1-4 >99 Compound 1-6 87 Compound 2-1 >99 Compound 2-2 91Compound 3-1 >99 Compound 4-1 >99 Compound 4-2 >99 Compound 4-3 88Compound 5-1 88 Compound 5-2 >99 Compound 7-1 >99 Compound 7-2 >99Compound 9-1 >99 Compound 10-1 94 Compound 10-2 >99 Compound 10-3 >99Compound 11-1 99 Compound 11-5 >99 Compound 14-1 >99 Control compoundB >99 Control compound C >99 Control compound D 98 Control compound E 98Control compound F 94

2. IL-6 Production Inhibitory Action Evaluation Test

To evaluate the action of the present compounds as a GR agonist, IL-6production inhibitory action in human corneal epithelial cell line afterLPS stimulation was examined. The IL-6 production was measured by usingthe HTRF method (Cat No. 62IL6PEB manufactured by Cisbio Bioassays,Inc.) according to the attached protocol. The specific method isdescribed below.

(Preparation of Reagent)

LPS solution: After dissolving LPS in PBS(−), the resulting solution wasdiluted with a culture solution, whereby an LPS solution with a 1 μg/mLconcentration was prepared.

(Preparation of Test Compound Solution and DEX Solution)

After dissolving the test compound in dimethylsulfoxide, the solutionwas diluted with a 10% FBS-DMEM/Ham's F12 medium, whereby a 100 μM ofthe test compound solution was prepared. When the IC₅₀ value is to becalculated, the 100 μM solution was diluted with a 1%dimethylsulfoxide-containing 10% FBS-DMEM/Ham's F12 medium, whereby 10μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM and 0.01 μM of the test compoundsolutions were prepared, respectively. In addition, DEX was similarlydissolved, whereby a 100 μM concentration of the DEX solution wasprepared, and an IL-6 production inhibitory ratio of DEX was measured,and used for calculation of Efficacy (% DEX).

(Used Cells and Culturing Method)

Used cells: human corneal epithelium cell line (HCE-T) (RIKEN, Instituteof Physical and Chemical Research)

Culturing Method

1) HCE-T proliferated to a subconfluent state was washed with PBS(−),and the cells were detached by the trypsin-EDTA treatment.2) SHEM medium (supplemented hormone epithelial medium: 15% FBS, 5 μg/mLof insulin, 10 ng/mL of human EGF, and 40 μg/mL of gentamicin-containingDMEM/Ham's F12) was added and trypsin was inactivated.3) The above suspension was recovered, and centrifuged by 1,000 rpm for5 minutes to give a cell sediment.4) The cell sediment was suspended by an SHEM medium, seeded in aculture flask, and cultured in a CO₂ incubator (temperature: 37° C., CO₂concentration: 5%). The cells continued to subculture according to thismethod were used for the test.

(Test Method and Measurement Method)

1) The subcultured HCE-T was recovered and the cells were seeded at2.0×10⁴ cells/0.1 mL/well in a 96-well flat bottom culture plate.2) After culturing overnight, medium the medium was removed and each 80μL/well of 10% FBS-DMEM/Ham's F12 medium was added.3) Test compound solution was added with each 10 μL/well.4) LPS solution was added with each 10 μL/well.5) The sample to which 1% dimethylsulfoxide-containing 10%FBS-DMEM/Ham's F12 medium was added with each 10 μL/well in place ofeach test compound solution, and 10% FBS-DMEM/Ham's F12 medium was addedin place of the LPS solution was made a negative control.6) The sample in which 1% dimethylsulfoxide-containing 10%FBS-DMEM/Ham's F12 medium was added with each 10 μL/well in place ofeach test compound solution was made a positive control.7) After completion of 4 hours cultivation, the supernatant wasrecovered and the amount of IL-6 released in the supernatant wasmeasured by using an HTRF human IL-6 Kit.8) The IL-6 production inhibitory ratio was calculated according to thefollowing calculation formula.

(Calculation of IL-6 Production Inhibitory Ratio)

The IL-6 production inhibitory ratio (%) was calculated by the followingformula.

IL-6 production inhibitory ratio(%)=100×{1−(IL-6 produced amount of eachtest compound solution−average value of IL-6 produced amount of negativecontrol group)/(average value of IL-6 produced amount of positivecontrol group−average value of IL-6 produced amount of negative controlgroup)}(%)

Further, the IL-6 production inhibitory ratio (Efficacy (% DEX)) whenthe DEX treated group was made 100 was calculated.

Efficacy(% DEX)=100×{(average value of IL-6 production inhibitory ratioof each test compound solution)/(average value of IL-6 productioninhibitory ratio of DEX treated group)}(%)

In addition, IC₅₀ was calculated according to a conventional method.IDBS XLfit4 was used for the calculation.

(Test Result and Consideration)

The IL-6 production inhibitory ratio (% DEX) and IC₅₀ (μM) when thecompound 1-1, the compound 1-4, the compound 1-6, the compound 2-1, thecompound 5-1, the compound 5-2, the compound 7-2, the compound 11-4, thecompound 11-5, the control compound B, the control compound C, thecontrol compound D, the control compound E and the control compound Fwere used as the test compounds are shown in Table II.

As a result of the IL-6 production inhibitory action evaluation test,the present compounds showed an excellent IL-6 production inhibitoryaction.

TABLE II IL-6 production inhibitory ratio Test compound (% DEX) IC₅₀(μM) Compound 1-1 86 0.033 Compound 1-4 92 0.034 Compound 1-6 89 <0.001Compound 2-1 82 0.015 Compound 5-1 98 0.014 Compound 5-2 >99 0.013Compound 7-2 >99 0.083 Compound 11-4 94 Not measured Compound 11-5 94Not measured Control compound B 62 0.123 Control compound C 71 0.093Control compound D 69 Not measured Control compound E 10 Not measuredControl compound F 62 Not measured

3. TNFα Production Inhibitory Action Evaluation Test

In order to evaluate an action of the present compound as a GR agonist,a TNFα production inhibitory action in rat whole blood after LPSstimulation ex vivo was investigated. For the measurement of the TNFαproduction amount, the ELISA method (manufactured by R&D Systems, CatNo. RTA00) was used, and a procedure was carried out according to theprotocol attached thereto. Hereinafter, the specific method will bedescribed.

(Preparation of Reagent)

LPS solution: LPS was dissolved in PBS(−) and diluted with RPMI 1640 toprepare an LPS solution with a concentration of 2 μg/mL.

(Preparation of Test Compound Solution and DEX Solution)

After the test compound was dissolved in dimethylsulfoxide, the solutionwas diluted with PBS(−) to prepare 200 μM of a test compound solution.In addition, DEX was similarly dissolved to prepare 200 μM of a DEXsolution, and a TNFα production inhibitory ratio of DEX was measured,and used for calculation of Efficacy (% DEX).

(Test Method and Measurement Method)

1) Blood was collected from 3 to 5 rats using an injection syringetreated with heparin from the abdominal aorta under isofluraneanesthesia. The rats confirmed death after lething the whole blood.2) The blood of 3 to 5 rats pooled in a 96-well round bottom cultureplate was seeded at each 180 μL/well.3) It was cultured (37° C., 5% CO₂, 95% air) for about 1 hour.4) The test compound solution was added each 10 μL/well, and culturedfor 1 hour.5) LPS solution was added each 10 μL/well.6) The sample in which 2% dimethylsulfoxide-containing PBS(−) was addedwith each 10 μL/well in place of each test compound solution, and RPMI1640 was added with each 10 μL/well in place of the LPS solution wasmade a negative control.7) The sample in which 2% dimethylsulfoxide-containing PBS(−) was addedwith each 10 μL/well in place of each test compound solution was made apositive control.8) After completion of 20 hours cultivation, the supernatant wasrecovered and the amount of TNFα released in the supernatant wasmeasured by using an ELISA Kit.9) The TNFα production inhibitory ratio was calculated according to thefollowing calculation formula.

(Calculation of TNFα Production Inhibitory Ratio)

TNFα production inhibitory ratio (%) was calculated according to thefollowing formula.

TNFα production inhibitory ratio(%)=100×{1−(TNFα production amount ofeach test compound solution−average value of TNFα production amount ofnegative control group)/(average value of TNFα production amount ofpositive control group−average value of TNFα production amount ofnegative control group)}(%)

Further, a TNFα production inhibitory ratio (Efficacy (% DEX)) when theDEX treated group was made 100 was calculated.

Efficacy(% DEX)=100×{(average value of TNFα production inhibitory ratioof each test compound solution)/(average value of TNFα productioninhibitory ratio of DEX treated group)}(%)

(Test Result and Consideration)

The TNFα production inhibitory ratios (Efficacy (% DEX)) when thecompound 1-1, the compound 1-2, the compound 1-3, the compound 1-4, thecompound 2-1, the compound 2-2, the compound 5-2, the compound 10-2, thecompound 14-1, the control compound B, the control compound E and thecontrol compound F were used as the test compound are shown in TableIII.

As a result of the TNFα production inhibitory action evaluation test,the present compounds showed excellent TNFα production inhibitoryaction.

TABLE III TNFα production inhibitory ratio Test compound (% DEX)Compound 1-1 81 Compound 1-2 94 Compound 1-3 93 Compound 1-4 94 Compound2-1 97 Compound 2-2 95 Compound 5-2 >99 Compound 10-2 >99 Compound 14-186 Control compound B 77 Control compound E 0 Control compound F 69

4. IL-2 and IL-4 Production Inhibitory Actions Evaluation Test

In order to evaluate an action of the present compound as a GR agonist,IL-2 and IL-4 production inhibitory actions in a normal human CD4+ Tcell after stimulation by an anti-CD3/CD28 antibody were investigated.For the measurement of the IL-2 and IL-4 production amounts, the ELISAmethod (manufactured by R&D Systems, Cat No. D2050, HS400) was used, anda procedure was carried out according to the protocol attached thereto.Hereinafter, the specific method will be described.

(Preparation of Reagent)

Dynabeads (Registered Trademark) Human T-Activator CD3/CD28 (4×10⁷beads/mL) (Dynabeads) was used, and prepared according to the protocolattached thereto.

(Preparation of Test Compound Solution)

After the test compound was dissolved in dimethylsulfoxide, the solutionwas diluted with an RPMI medium to prepare 400 μM of a test compoundsolution. The solution was diluted with a 4%dimethylsulfoxide-containing RPMI medium to prepare 40 μM of a testcompound solution.

(Used Cells and Culturing Method)

Used cells: normal peripheral blood human CD4+ T cell (human CD4+ Tcell) (Lonza) Culturing method:

1) Frozen human CD4+ T cells were thawed in a warm water bath at 37° C.,and added to an RPMI medium (RPMI 1640 containing 10% FBS, 100 U/mL ofPenicillin, and 100 μg/mL of Streptomycin).2) The above suspension was recovered and centrifuged at 900 rpm for 10minutes to give a cell sediment.3) The cell sediment was suspended in an RPMI medium and the operationof 2) was carried out.4) The cell sediment was adjusted to 4×10⁵ cells/mL with an RPMI medium.5) The above suspension was cultured in a CO₂ incubator (temperature:37° C., CO₂ concentration: 5%) for 1 hour or longer.

(Test Method and Measurement Method)

1) The cultured human CD4+ T cells were recovered and the cells wereseeded in 96-well flat bottom culture plates at each 8.0×10⁴ cells/0.2mL/well.2) The test compound solution was added with each 5 μL/well.3) The prepared Dynabeads were added with each 2 μL/well.4) The sample in which 4% dimethylsulfoxide-containing RPMI medium wasadded with each 5 μL/well in place of each test compound solution, andthe RPMI medium was added with each 2 μL/well in place of the Dynabeadswas made a negative control.5) The sample in which 4% dimethylsulfoxide-containing RPMI medium wasadded with each 5 μL/well in place of each test compound solution wasmade a positive control.6) After completion of 24 hours cultivation, the supernatant wasrecovered and the amounts of IL-2 and IL-4 released in the supernatantwas measured by using an ELISA Kit.7) The IL-2 and IL-4 production inhibitory ratios were calculatedaccording to the following calculation formula.

(Calculation of IL-2 and IL-4 Production Inhibitory Ratios)

The IL-2 and IL-4 production inhibitory ratios (%) were calculated bythe following formula, respectively.

IL-2 or IL-4 production inhibitory ratio(%)=100×{1−(IL-2 or IL-4production amounts of each test compound solution−average value of IL-2or IL-4 production amount of negative control group)/(average value ofIL-2 or IL-4 production amount of positive control group−average valueof IL-2 or IL-4 production amount of negative control group)}(%)

(Test Result and Consideration)

The IL-2 and IL-4 production inhibitory ratios (% of 1 μM) when thecompound 1-1, the compound 2-1, the compound 11-1, the control compoundB, the control compound C, the control compound D, the control compoundE and the control compound F were used as the test compounds are shownin Table IV.

As a result of the IL-2 and IL-4 production inhibitory action evaluationtest, the present compounds showed excellent IL-2 and IL-4 productioninhibitory actions.

TABLE IV IL-2 production IL-4 production inhibitory ratio inhibitoryratio Test compound (% of 1 μM) (% of 1 μM) Compound 1-1 73 91 Compound2-1 79 83 Compound 11-1 72 87 Control compound B 35 51 Control compoundC 26 56 Control compound D <0 46 Control compound E <0 32 Controlcompound F <0 29

5. MCP-1 Production Inhibitory Action Evaluation Test

In order to evaluate an action of the present compound as a GR agonist,an MCP-1 production inhibitory action in human monocyte cell afterstimulation by LPS was investigated. For the measurement of the MCP-1production amount in the sample, the ELISA method (manufactured by R&DSystems, Cat No. DCP00) was used, and a procedure was carried outaccording to the protocol attached thereto. Hereinafter, the specificmethod will be described.

(Preparation of Reagent)

LPS solution: After LPS was dissolved in PBS(−), the solution wasdiluted with 10% FBS-containing RPMI 1640 to prepare an LPS solutionwith a 40 μg/mL concentration.

(Preparation of Test Compound Solution)

After the test compound was dissolved in dimethylsulfoxide, the solutionwas diluted with an RPMI medium to prepare 400 μM of a test compoundsolution. The solution was diluted with a 4%dimethylsulfoxide-containing RPMI 1640 medium to prepare 40 μM of a testcompound solution.

(Used Cells and Culturing Method)

Used cells: human monocyte cell (THP-1) (ATCC)

Culturing Method

1) Subcultured THP-1 was recovered and centrifuged at 1,100 rpm for 5minutes to give a cell sediment.2) An RPMI medium (RPMI 1640 containing 10% FBS, 100 U/mL of penicillin,100 μg/mL of streptomycin, 55 μM of 2-Mercaptoethanol, 10 ng/mL of humanEGF, and 40 μg/mL of gentamicin) was added.3) The above suspension was seeded in a culture flask and cultured in aCO₂ incubator (temperature: 37° C., CO₂ concentration: 5%). The cellscontinued to subculture according to this method were used for the test.

(Test Method and Measurement Method)

1) The subcultured THP-1 was recovered and the cells were each seeded at1.9×10⁵ cells/0.19 mL/well in a 96-well round bottom culture plate.2) The test compound solution was added with each 5 μL/well and culturedfor 2 hours.3) LPS solution was added with each 5 μL/well.4) The sample to which 4% dimethylsulfoxide-containing RPMI medium wasadded with each 5 μL/well in place of each test compound solution, and10% FBS-RPMI 1640 was added with each 5 μL/well in place of the LPSsolution was made a negative control.5) The sample to 4% dimethylsulfoxide-containing RPMI medium was addedwith each 5 L/well in place of each test compound solution was made apositive control.6) After completion of 18 hours cultivation, the supernatant wasrecovered and the amount of MCP-1 released in the supernatant wasmeasured by using an ELISA Kit.7) The MCP-1 production inhibitory ratio was calculated according to thefollowing calculation formula.

(Calculation of MCP-1 Production Inhibitory Ratio)

MCP-1 production inhibitory ratio (%) was calculated by the followingformula.

MCP-1 production inhibitory ratio(%)=100 ×{1−(MCP-1 production amount ofeach test compound solution−average value of MCP-1 production amount ofnegative control group)/(average value of MCP-1 production amount ofpositive control group−average value of MCP-1 production amount ofnegative control group)}(%)

(Test Result and Consideration)

The MCP-1 production inhibitory ratios (% of 1 μM) when the compound1-1, the compound 2-1, the compound 11-1, the control compound B, thecontrol compound C, the control compound E and the control compound Fwere used as the test compounds are shown in Table V.

As a result of the MCP-1 production inhibitory action evaluation test,the present compounds showed an excellent MCP-1 production inhibitoryaction.

TABLE V MCP-1 production inhibitory ratio Test compound (% of 1 μM)Compound 1-1 86 Compound 2-1 91 Compound 11-1 88 Control compound B 65Control compound C 65 Control compound E 40 Control compound F 27

From the above results, the present compounds are confirmed to be usefulas a GR agonist than the control compounds, and to be useful as adisease to which the GR agonist such as a steroid is effective, inparticular, as a prophylactic or therapeutic agent for inflammatorydiseases (bone and joint diseases, ocular inflammatory diseases, or thelike).

6. Conjunctivitis Model Evaluation Test

In order to evaluate an anti-inflammatory action of the present compoundto conjunctivitis, an inhibitory effect on edema formation in acarrageenin-caused conjunctivitis model of rats was investigated.Incidentally, this effect was evaluated by calculating an edemaformation inhibitory ratio from a weight of the edema in a base agentadministered group (control group) and a weight of the edema in the testcompound administered group.

(Preparation of Eye Drop Solution of Test Compound)

A base agent containing a general additive(s) was added to the testcompound to prepare test compound suspensions with 0.001% (W/V), 0.003%(W/V), 0.01% (W/V) and 1% (W/V).

(Preparation of Carrageenin-Caused Conjunctivitis Model and EvaluationMethod)

By using male Wistar/ST rats, a urethane solution was administered andgeneral anesthesia was applied, then a physiological saline solution inwhich 1.0% (W/V) of carrageenan had been dissolved was injected into theupper palpebral conjunctiva with both eyes each in an amount of 50μL/eye to induce inflammation.

The compound 1-1 was once eye dropped (instillation dose: 5 μL/time) toboth eyes 30 minutes before induction. In the base agent administeredgroup (control group), the base agent was similarly eye dropped. Thecontrol compounds B and C were eye dropped (instillation dose: 5μL/time) five times in total from 1 hour before induction to 3 hoursafter induction with an interval of 1 hour. In the base agentadministered group (control group), the base agent was similarly eyedropped.

Four hours after induction, rats under general anesthesia weresacrificed by decapitation method, conjunctival edema areas of both eyeswere removed, and the weight of each was measured. The edema formationinhibitory ratio was calculated from the average value of the weight ofthe edema.

(Calculation of Inhibitory Ratio)

Based on the average value of the weight of the edema of the base agentadministered group (control group), the edema formation inhibitory ratioof the test compound suspension eye drop group was calculated by thefollowing calculation formula.

Edema formation inhibitory ratio(%)=100×{1−(average value of the weightof the edema in the test compound eye drop group)/(average value of theweight of the edema in the base agent administered group (controlgroup))}(%)

(Test Result and Consideration)

The edema formation inhibitory ratios (%) when the compound 1-1, thecontrol compound B, the control compound C, commercially available drugA (active ingredient: 0.5% loteprednol etabonate) and commerciallyavailable drug B (active ingredient: 0.1% fluorometholone) which areexisting ophthalmic solutions were used as the test compounds are shownin Table VI. The average value of the weight of the edema is each 8 to10 eyes (4 to 5 rats).

As a result of the conjunctivitis model evaluation test, the presentcompounds showed an excellent edema formation inhibitory effect.

TABLE VI Edema formation Test compound inhibitory ratio (%) Compound 1-1(0.001%) 26 Compound 1-1 (0.003%) 30 Compound 1-1 (0.01%) 37 Controlcompound B (1%) 14 Control compound C (1%) 14 Commercially availabledrug A (0.5%) 33 Commercially available drug B (0.1%) 37

From the above results, the present compounds are confirmed to be usefulas a treatment agent for anterior eye inflammatory diseases, inparticular, as a prophylactic or therapeutic agent for ocularinflammatory diseases such as keratitis, keratoconjunctivitis,conjunctivitis, inflammation by blepharitis, or the like.

7. Anterior Eye Inflammation Model Evaluation Test

In order to evaluate an anti-inflammatory action of the present compoundon anterior eye inflammation, an inhibitory effect on a number ofinfiltrated cells into aqueous humor in a paracentesis inducedintraocular inflammation model of rabbits was investigated.Incidentally, this effect was evaluated by calculating an inhibitoryratio from a number of infiltrated cells into aqueous humor in the baseagent administered group (control group) and a number of infiltratedcells into aqueous humor in the test compound administered group.

(Preparation of Eye Drop Solution of Test Compound)

A base agent containing a general additive(s) was added to the testcompound to prepare a test compound suspension with 3% (W/V).

(Preparation of Paracentesis Induced Intraocular Inflammation Model andEvaluation Method)

1) Male JW rabbits underwent local anesthesia with 0.4% oxybuprocainehydrochloride (trade name: Benoxil ophthalmic solution 0.4%), and about0.1 mL of anterior aqueous humor was collected by using a syringe fortuberculin so as not to touch the iris to carry out primary puncture,whereby an inflammatory response was induced.2) Thirty minutes before the primary puncture, heparin was intravenouslyadministered so as to be about 50 unit/kg.3) The test compound suspension was eye dropped (instillation dose: 50μL/time) to both eyes in total four times, 210 minutes before, 60minutes before, 15 minutes after, and 90 minutes after the primarypuncture. To the base agent administered group (control group), the baseagent was similarly eye dropped.4) 120 minutes after the primary puncture, about 1.5 mL/kg ofpentobarbital sodium (trade name: Somnopentyl) was intravenouslyadministered from the rabbit ear vein. Thereafter, about 0.1 mL ofanterior aqueous humor was collected by using a syringe for tuberculin,and the sample was stored in ice.5) The number of infiltrated cells into the aqueous humor was measuredusing a TC10 full-automatic cell counter (Bio-Rad).

(Calculation Formula)

Inhibitory ratio(%) of infiltrated cells into aqueous humor in the testcompound administered group=100×{1−(average value of the number ofinfiltrated cells into aqueous humor in the test compound eye dropgroup)/(average value of the number of infiltrated cells into aqueoushumor in the base agent administered group (control group))}(%)

(Test Result and Discussion)

The inhibitory ratio (%) of the number of infiltrated cells into aqueoushumor in the case where the compound 11-1 was used as the test compoundshowed 37%. Incidentally, the average value of the score is each 7 eyes(14 rabbits).

As a result of the anterior eye inflammation model evaluation test, thepresent compounds showed an excellent inhibitory effect on the number ofinfiltrated cells into aqueous humor.

From the above results, the present compounds are confirmed to be usefulas a treatment agent for anterior eye inflammatory diseases, inparticular, as a prophylactic or therapeutic agent for ocularinflammatory diseases such as uveitis, inflammation after surgery andinflammation due to rejection of ocular tissue transplantation, or thelike.

8. Dry Eye Syndrome (Dry Eye) Model Evaluation Test

In order to evaluate the treatment effect of the present compounds oncorneal disorder accompanied by dry eye syndrome (dry eye), a treatmenteffect on corneal disorder in an exorbital lacrimal gland-removed ratdry eye model was investigated. This model was prepared in accordancewith the method of Fujihara, et a1. (Invest. Ophthalmol. Vis. Sci.,42(1): 96-100 (2001)). Incidentally, this effect was scored according tothe method of Murakami et a1. (New Ophthalmologist 21(1): 87-90 (2004)),the extent of corneal disorder was scored and the improvement ratio wascalculated from the corneal disorder score of the base agentadministered group (control group), the corneal disorder score of thetest compound administered group and the corneal disorder score of thenormal rat.

(Preparation of Eye Drop Solution of Test Compound)

A base agent containing a general additive(s) was added to the testcompound to prepare test compound suspensions with 0.03% (W/V) and 0.1%(W/V). In addition, a base agent was added to the commercially availabledrug A to prepare a diluted solution with 0.05% (V/V).

(Preparation of Exorbital Lacrimal Gland-Removed Dry Eye Model andEvaluation Method)

1) By using male SD rats, somnopentyl was administered to the rats toapply them general anesthesia, exorbital lacrimal glands were removed,and corneal disorder was induced over 8 weeks thereafter.2) The test compound suspension was eye-dropped (instillation dose: 5μL/time) to both eyes four times a day for 14 days. Incidentally, thebase agent was similarly eye-dropped to the administered group (controlgroup), and the commercially available drug A and its diluted solutionwere similarly eye-dropped.3) Fourteen days after the start of eye dropping, the cornea was stainedwith fluorescein. For each of the upper part, the middle part and thelower part of the cornea, scores of the degree of staining withfluorescein were determined according to the following criteria, and anaverage value of the total of the scores was calculated. Incidentally,0.5 was set as an intermediate value between each score of 0, 1, 2 and3.

<<Judgement Standard>>

0: not dyed

1: Dyeing is sparse, and the dyed portions of each dot are separated

2: Dyeing is a middle degree and part of the dotted dyed portions isadjacent

3: Dyeing is dense, and the dyed portions of each point are almostadjacent

(Calculation Formula)

Corneal disorder improvement ratio(%) of the test compound administeredgroup=(Ao−Ax)/(Ao−An)×100

Ao: Average value of corneal disorder score of the base agentadministered group (control group)Ax: Average value of corneal disorder score of the test compoundadministered groupAn: Average value of corneal disorder score of normal rat

(Test Result and Consideration)

The corneal disorder improvement ratios (%) when the compound 1-1, thecompound 2-1, the compound 11-1, the compound 12-1, the compound 13-1,the commercially available drug A (active ingredient: 0.5% loteprednoletabonate) which is existing ophthalmic solution and a diluted solutionof the commercially available drug A were used as the test compounds areshown in Table VII. Incidentally, the average value of the score is each8 eyes (4 rats).

As a result of the dry eye syndrome (dry eye) model evaluation test, thepresent compounds showed an excellent corneal disorder improvementratio.

TABLE VII Corneal disorder Corneal disorder improvement improvementratio (%) ratio (%) After 7 days After 14 days Test compound eyedropping eye dropping Compound 1-1 (0.03%) 22 41 Compound 1-1 (0.1%) 3661 Compound 2-1 (0.1%) 40 45 Compound 11-1 (0.03%) 35 33 Compound 11-1(0.1%) 44 64 Compound 12-1 (0.03%) 33 48 Compound 12-1 (0.1%) 42 58Compound 13-1 (0.1%) 38 46 Commercially available drug A 21 38 dilutedsolution (0.05%) Commercially available drug A 54 54 (0.5%)

From the above results, the present compounds are confirmed to be usefulas a treatment agent for anterior eye inflammatory diseases, inparticular, as a prophylactic or therapeutic agent for ocularinflammatory diseases such as keratitis, keratoconjunctivitis,conjunctivitis, blepharitis, dry eye syndrome (dry eye), or the like.

9. Allergic Conjunctivitis Model Evaluation Test

In order to evaluate an anti-allergic action of the present compounds onallergic conjunctivitis, an inhibitory effect on hyperemia in anovalbumin actively sensitized allergic conjunctivitis model of rabbitswas investigated. Incidentally, this effect was evaluated by calculatingan inhibitory ratio from the score of the base agent administered group(control group) and the score of the test compound administered group.

(Preparation of Eye Drop Solution of Test Compound)

A base agent containing a general additive(s) was added to the testcompound to prepare test compound suspensions with 1% (W/V) and 3%(W/V).

(Preparation of Ovalbumin Actively Sensitized Allergic ConjunctivitisModel and Evaluation Method)

By using male JW rabbits, ovalbumin (200 μg/mL/physiological salinesolution) adsorbed on aluminum hydroxide gel was injected 200 μL per eyeinto bulbar conjunctiva of both eyes of rabbits, respectively, toperform active sensitization.

After 14 days from sensitization or later, the test compound suspensionwas eye-dropped four times a day for 4 days, and then, at the next day,it was eye-dropped (instillation dose: 50 μL/time) once to both eyes.Incidentally, the base agent was similarly eye-dropped to the base agentadministered group (control group).

One hour after the final eye dropping of the test compound suspension, aphysiological saline solution containing 0.02% (W/V) of ovalbumin wasadministered from rabbit ear vein at a dose of 1.5 mL per 1 kg of rabbitto induce allergic conjunctivitis.

After 0.5 hour of the challenge, the degree of hyperemia symptoms ofboth ocular conjunctiva of rabbits was evaluated according to thefollowing criteria, and the average value of the total of these scoreswas calculated.

<<Judgement Standard>>

0: No findings

1: A state in which several expanded blood vessels are observed in partof the superior rectus muscle of the eyeball or the corneal limbus

2: A state in which many expanded blood vessels are observed in thesuperior rectus muscle of the eyeball, or a state in which severalexpanded blood vessels are observed in the superior rectus muscle of theeyeball and expansions of several blood vessels are observed in part ofthe corneal limbus

3: A state in which a large number of expanded blood vessels areobserved the superior rectus muscle of the eyeball and in part of thecorneal limbus

4: A state in which a large number of expanded blood vessels areobserved the superior rectus muscle of the eyeball and all around thecorneal limbus

5: A state in which expanded blood vessels are observed on the superiorrectus muscle of the eyeball, the entire circumference of the corneallimbus, and on the other ocular conjunctiva

(Calculation Formula)

Inhibitory ratio(%) of hyperemia of the test compound administeredgroup={(Ao−Ap)−(Ax Ap1)−(Ax−Ap2)}/(Ao−Ap1)×100

Ao: Average value of hyperemia score of the base agent administeredgroup (control group)Ax: Average value of hyperemia score of the test compound administeredgroupAp1: Average value of hyperemia score before challenge of the base agentadministered groupAp2: Average value of hyperemia score before challenge of the testcompound administered group

(Test Result and Consideration)

The hyperemia inhibitory ratios (%) when the compound 1-1, the compound2-1, the compound 5-2, the compound 11-1 and the compound 14-1 were usedas the test compounds are shown in Table VIII. Incidentally, the averagevalue of the score is each 8 eyes (8 rabbits).

As a result of the allergic conjunctivitis model evaluation test, thepresent compounds showed an excellent hyperemia inhibitory effect.

TABLE VIII Test compound Eye congestion inhibitory ratio (%) Compound1-1 (1%) 35 Compound 2-1 (1%) 29 Compound 5-2 (3%) 35 Compound 11-1 (1%)44 Compound 14-1 (1%) 22

From the above results, the present compounds are confirmed to be usefulas a treatment agent for anterior eye inflammatory diseases, inparticular, as a prophylactic or therapeutic agent for ocularinflammatory diseases such as keratitis, keratoconjunctivitis,conjunctivitis, blepharitis, dry eye syndrome (dry eye), allergicconjunctivitis, or the like.

10. Retinal Vascular Permeability Model Evaluation Test

In order to evaluate the inhibitory effect of the present compounds onVEGF-induced retinal vascular permeability, the inhibitory effect of thepresent compound on retinal vascular permeability in a VEGF-inducedretinal elevated vascular permeability model of rabbits was evaluated.Incidentally, this effect was evaluated by calculating a leaked amountof the fluorescent dye of the base agent administered group (non-inducedgroup), a leaked amount of the fluorescent dye of the base agentadministered group (control group) and a leaked amount of thefluorescent dye of the test compound administered group.

(Preparation of Test Compound Suspension or Test Compound Solution)

To the test compound was added 0.01% Polysorbate 80/0.5% sodiumcarboxymethyl cellulose/PBS (hereinafter referred to as “base agentA”.), whereby 2% (W/V) or 8% (W/V) of the test compound suspension wasprepared. Or else, to the test compound was added PEG400 (hereinafterreferred to as “base agent B”.), whereby 6% (W/W) of the test compoundsolution was prepared.

(Preparation of Reagent)

VEGF solution: humanVEGF165 was dissolved in PBS to prepare 50 μg/mL ofVEGF solution.

(Preparation of VEGF-Induced Retinal Vascular Permeability Model andEvaluation Method)

1) A mixed solution (1 mL/kg) of 5% ketamine hydrochloride injectionsolution and 2% xylazine hydrochloride injection solution with the ratioof 7:1 was intramuscularly administered to rabbits (Dutch male rabbits),and the rabbits were anesthetized.2) Tropicamide-phenylephrine hydrochloride ophthalmic solution (tradename: Midlin P) was eye dropped to maintain pupillary mydriasis, andthen, the VEGF solution was intravitreally administered. Incidentally,PBS was intravitreally administered to the base agent administrationgroup (non-induced group).3) Fluorescein was intravenously administered 2 days after intravitrealadministration of VEGF. Two hours after the intravenous administrationof fluorescein, an amount of the leaked fluorescent dye in the vitreousbody was measured by using a fluorophotometer.

(Test Method)

1) One week before or 4 weeks before VEGF-induction, 50 μL of the testcompound suspension (prepared by the base agent A) was intravitreallyadministered once, or 5 μL of the test compound solution (prepared bythe base agent B) was intravitreally administered once. Incidentally, inthe base agent administered group (non-induced group) and the base agentadministered group (control group), the base agent A was used in placeof the test compound suspension, or the base agent B was used in placeof the test compound solution.2) Inhibition ratio of elevated retinal vascular permeability wascalculated according to the following calculation formula.

(Calculation Formula)

Inhibitory ratio(%) on elevated retinal vascular permeability of thetest compound administered group=100×{1−(average value of a leakedfluorescent dye amount in the test compound administered group−averagevalue of a leaked fluorescent dye amount in the base agent administeredgroup (non-induced group))/(average value of a leaked fluorescent dyeamount in the base agent administered group (control group)−averagevalue of a leaked fluorescent dye amount of the base agent administeredgroup (non-induced group))}

(Test Result and Consideration)

The inhibitory ratios (%) on elevated retinal vascular permeability whenthe compound 1-1, the compound 2-1, the compound 5-2, the compound 11-2,the compound 14-3, the control compound B, the control compound D andthe control compound E were used as the test compounds are shown inTable IX. Incidentally, the average value of the leaked fluorescent dyeamount is each 4 to 6 eyes (2 to 3 rabbits).

As a result of the retinal vascular permeability model evaluation test,the present compounds showed an excellent inhibitory effect on elevatedretinal vascular permeability.

TABLE IX Inhibitory Term from ratio (%) on administration elevatedAdministration of test compound vascular Test compound dose/base agentto induction permeability Compound 1-1 6% 5 μL/B 4 weeks 80 Compound 2-12% 50 μL/A 1 week >99 Compound 2-1 2% 50 μL/A 4 weeks 91 Compound 5-2 2%50 μL/A 1 week 96 Compound 5-2 2% 50 μL/A 4 weeks 91 Compound 11-2 2% 50μL/A 4 weeks 92 Compound 14-3 8% 50 μL/A 4 weeks 89 Control compound B2% 50 μL/A 1 week 36 Control compound D 2% 50 μL/A 4 weeks 38 Controlcompound E 2% 50 μL/A 1 week 47

From the above results, the present compounds are confirmed to be usefulas a treatment agent for posterior eye inflammatory disease, inparticular, as a prophylactic or therapeutic agent for age-relatedmacular degeneration, diabetic macular edema, central retinal veinocclusion, branch retinal vein occlusion, or the like.

PREPARATION EXAMPLES

A general Preparation example of the present compound is shown below.

Preparation Example 1: Tablet In 150 mg

Present compound   1 mg Lactose 100 mg  Corn starch  40 mg Calciumcarboxymethyl cellulose 4.5 mg Hydroxypropyl cellulose   4 mg Magnesiumstearate 0.5 mg

The tablet of the above-mentioned prescription was subjected to coatingby using 3 mg of a coating agent (for example, a coating agent generallyused such as hydroxypropylmethyl cellulose, macrogol, a silicone resin,or the like) to obtain the intended tablet. In addition, a desiredtablet may also be obtained by optionally changing the present compound,the kind of the additives and/or the amount of the additives.

Preparation Example 2: Capsule In 150 mg

Present compound 5 mg Lactose 135 mg  Calcium carboxymethyl cellulose4.5 mg   Hydroxypropyl cellulose 4 mg Magnesium stearate 1.5 mg  

A desired capsule may also be obtained by optionally changing thepresent compound, the kind of the additives and/or the amount of theadditives.

Preparation Example 3: Ophthalmic Agent In 100 mL

Present compound 100 mg Sodium chloride 900 mg Polysorbate 80 500 mgSodium hydroxide q.s. Hydrochloric acid q.s. Sterile purified water q.s.

Preparation Example 4: Intravitreal Administration Agent In 100 mL

Present compound 100 mg Polyethylene glycol 400 q.s.

A desired ophthalmic agent may also be obtained by optionally changingthe present compound, the kind of the additives and/or the amount of theadditives.

INDUSTRIAL APPLICABILITY

The novel[4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl)-phenoxy]ethyloxycompound or a salt thereof according to the present invention has theglucocorticoid receptor agonist activity, and useful as a prophylacticor therapeutic agent of a disease, in particular, glucocorticoidreceptor related disease, as a medicine.

1. A compound of(S)-7-[4-[2-(N,N-dimethylaminoacetoxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,or a pharmaceutically acceptable salt or a hydrate or a solvate thereof.2. A compound of(R)-7-[4-[2-(N,N-dimethylaminoacetoxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,or a pharmaceutically acceptable salt or a hydrate or a solvate thereof.3. A compound of(S)-7-[4-(2-aminoacetoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,or a pharmaceutically acceptable salt or a hydrate or a solvate thereof.4. A compound of(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-phosphonohydroxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,or a pharmaceutically acceptable salt or a hydrate or a solvate thereof.